Stability of various total nutrient admixture formulations using Liposyn II and Aminosyn II

The compatibility of a safflower oil-soybean oil lipid emulsion (Liposyn II) with dextrose and amino acid injection (Aminosyn II) with or without electrolytes was studied in total nutrient admixtures (TNAs). The admixtures studied were divided into two groups. In group 1, 15 admixtures representing six different combinations of Liposyn II, Aminosyn II, and dextrose injection were studied. In group 2, nine admixtures representing nine combinations of Liposyn II, Aminosyn II with Electrolytes, and dextrose injection were studied. Both 10% and 20% concentrations of the fat emulsion, amino acid concentrations of 7, 8.5, and 10%, and dextrose injections of 10, 40, 50, and 70% were used. The core admixture components were placed in an ethylene vinyl acetate container in the following sequence: fat, amino acids, dextrose. One of two combinations of electrolytes and trace metals was added to each admixture at the end of mixing. Multivitamins were added to each TNA just before 24-hour storage at room temperature (25 +/- 4 degrees C). Four admixtures were tested after one day at room temperature, six after two days at 5 degrees C plus one day at 30 degrees C, and 14 after nine days at 5 degrees C plus one day at room temperature. Measurements of pH, emulsion particle size, and zeta potential (electrostatic surface charge of lipid particles) were made after visual inspection of each admixture. Concentration of individual amino acids and dextrose were determined by appropriate chromatographic techniques initially and at the end of the storage period. The TNAs retained a uniform, milk-like appearance under all storage conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stability of total nutrient admixtures using various intravenous fat emulsions

The stability of four lipid emulsions with amino acids and dextrose in total nutrient admixtures (TNAs) was studied. The admixtures were divided into three groups. In group 1, 24 admixtures representing 20 different combinations of Liposyn II (safflower oil-soybean oil fat emulsion) with various manufacturers' amino acids (FreAmine III, Travasol, Novamine, Nephramine, and RenAmin) were tested. In group 2, 19 TNAs representing 14 combinations containing soybean-oil emulsions (Intralipid, Travamulsion, and Soyacal) and Aminosyn II amino acids were studied. In group 3, 14 TNAs representing 9 combinations containing the above soybean oil emulsions and Aminosyn II with Electrolytes were tested. Both 10% and 20% concentrations of fat emulsion, various amino acid concentrations ranging from 5.4% to 11.4%, and dextrose injections of 10, 20, 40, 50, and 70% were used. The admixtures were compounded in an ethylene vinyl acetate container. The mixing sequence involved transfer of fat emulsion to the empty container, followed by amino acids and dextrose. One of two electrolyte and trace metal profiles was added to each core admixture after compounding. Multivitamins were added just before the 24-hour room-temperature (25 +/- 4 degrees C) storage. Admixtures were tested initially and after one day at room temperature or nine days at 5 degrees C plus one day at room-temperature storage. Measurements of pH, emulsion particle size, osmolality, and zeta potential (electrostatic surface charge of lipid particles) were made after visual inspection of each admixture. In general, the TNAs retained a uniform, milk-like appearance under both storage conditions. The values of pH, zeta potential, particle size, and osmolality remained essentially unchanged throughout the study. Under the conditions of this study, the TNA formulations tested are stable for up to 10 days.     

Fat emulsion particle-size distribution in total nutrient admixtures.

The fat particle-size distribution in and physical stability of two commercially available lipid emulsions before and after their use in total nutrient admixtures (TNAs) are reported. Four TNAs without electrolytes and four TNAs with electrolytes were prepared; each type of TNA was prepared with Liposyn II and with Intralipid. Particle size was measured in the < 1-micron range by using photon correlation spectroscopy and in the 2-60-microns range by using light blockage. Admixtures with or without electrolytes were stored for two or nine days at 4 degrees C followed by one day at 25 degrees C. For the fraction of fat particles of < 1 micron in diameter, Intralipid and Liposyn II had a mean particle size of 374 and 313 nm, respectively. The admixtures containing electrolytes showed a decrease in mean particle size of about 7%. Admixtures with Intralipid contained 2 x 10(7) particles larger than 2 microns per milliliter (1.7% of total fat), compared with 1 x 10(6) particles per milliliter (0.05-0.15% of total fat) for admixtures with Liposyn II. The addition of electrolytes increased the particle counts for Liposyn II-containing admixtures. Upon storage, Intralipid-containing admixtures with electrolytes showed an initial increase followed by a decrease in the mean diameter of particles of < 1 micron. All the admixtures were stable in terms of pH and visual appearance. Intralipid-containing admixtures with electrolytes showed a decrease in the number of particles in the 2-60-microns size range, while Liposyn II-containing admixtures with electrolytes showed an increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stability of ranitidine hydrochloride in total nutrient admixtures

The stability of ranitidine hydrochloride in total nutrient admixtures (TNAs) containing 5% intravenous fat emulsion was studied. A TNA containing lipids and glucose was prepared aseptically in three ethylene-vinyl acetate bags. Ranitidine hydrochloride 100 mg and 200 mg was added to two of the bags to yield concentrations of 50 micrograms/mL and 100 micrograms/mL, respectively. The third bag served as a control. At 0, 12, 24, 48, and 72 hours, the ranitidine content was measured by high-performance liquid chromatography, the pH of the admixtures was determined, and the bags were visually inspected for signs of color changes, creaming, or precipitates. Particle-size distribution was measured at 72 hours and compared with that in the control bag at time zero. No appreciable changes in pH occurred over 72 hours, and no visual changes were observed. At concentrations of 50 and 100 micrograms/mL of admixture, ranitidine hydrochloride activity declined approximately 80% during the study period. Approximately 10% of the initial concentration was lost in 12 hours. In both cases, there was no variation in particle-size distribution compared with that in the control bag at time zero. Ranitidine hydrochloride appears to be stable for up to 12 hours at room temperature in the admixtures studied, and the lipid emulsion apparently was not altered during this period by ranitidine.     

Stability of nizatidine in total nutrient admixtures.

The stability of nizatidine in total nutrient admixtures (TNAs) and the effect of the drug on the stability of lipid emulsions in the TNAs were studied. Duplicate 1476-mL amino acid-dextrose base solutions were prepared; nizatidine 300 mg was added to one. TNAs were prepared by adding to 75-mL samples of the base solutions Intralipid (KabiVitrum) or Liposyn II (Abbott) and sterile water as needed to achieve final lipid concentrations of 3% and 5%. Triplicate 100-mL samples for each lipid product and concentration were prepared; fat-free samples containing nizatidine were also studied. The theoretical final nizatidine concentration was 150 micrograms/mL. Samples were stored at 22 degrees C for 48 hours. Initially and at 12, 24, and 48 hours, the samples were visually inspected, tested for pH and particle-size distribution, and assayed by high-performance liquid chromatography for nizatidine concentration. No color change, precipitation, creaming, or oiling out was noted. For the 12 TNAs containing nizatidine, mean solution pH during the study was 5.88; stability of the lipid products requires pH values greater than or equal to 5.5. Particle-size distribution did not differ appreciably between the nizatidine-containing and drug-free TNAs. Nizatidine concentrations remained greater than 90% of the initial concentration. Nizatidine at a theoretical concentration of 150 micrograms/mL was stable for 48 hours at 22 degrees C in TNA solutions containing 3% and 5% Intralipid or Liposyn II and did not appear to affect lipid emulsion stability.     

Effect of various nutrient ratios on the emulsion stability of total nutrient admixtures

The emulsion stability of total nutrient admixtures (TNAs) containing various ratios of amino acids (AA):carbohydrate (CHO):fat (FAT) was studied. Eight different TNA formulations were prepared in duplicate using AA supplied as 8.5% crystalline AA (FreAmine III), CHO supplied as 70% dextrose injection, and FAT supplied as 10 or 20% lipid emulsion (Soyacal). The eight formulations represented AA:CHO:FAT ratios (v:v:v) of 2:1:1, 1:1:1, 1:1:1/2, and 1:1:1/4, respectively, with each lipid concentration. TNAs also contained identical concentrations of electrolytes, trace elements, vitamins, and heparin. TNAs were stored at 4 degrees C for 14 days and then at ambient temperature (22-25 degrees C) for another four days. All TNAs were analyzed for gross visual appearance, pH, osmolality, and particle size and distribution on day 0 and periodically throughout the study period. Particle size was measured by photon-correlation spectrometry and negative-phase light microscopy. Visual examination revealed the presence of creaming in all TNAs, which could be dispersed by gentle agitation. The pH of each TNA decreased slightly during the study period, while the osmolality showed little variation. The mean diameter of particles in the TNAs remained close to that in the original lipid emulsions; 95% of all particles in the TNAs were less than 0.454 micron in diameter, which is within the size range of natural lipid particles or chylomicrons. Based on examination of particle size, each TNA formulation was stable for 18 days under the conditions of this study.     

Growth of microorganisms in total nutrient admixtures

It has been reported that intravenous fat emulsions, because of their isotonicity and neutral pH, support microbial growth, but traditional parenteral nutrition solutions, being hypertonic and more acidic, are not as supportive. To date, few studies have documented microbial growth in total nutrient admixtures (TNA) containing dextrose, amino acids, fat, electrolytes, vitamins, and trace elements. This study was undertaken to analyze the growth of Staphylococcus aureus, Candida albicans and four gram-negative enteric bacilli in three different nutrient admixtures, with and without the inclusion of 5% fat emulsion. The composition of the admixtures was either 5, 10, or 25% dextrose; either 0 or 5% fat; and 3% amino acids, electrolytes, vitamins, and trace elements. All admixtures were innoculated with 100 colony-forming units per milliliter, incubated at room (25 degrees C) or refrigerated (4 degrees C) temperature, with samples withdrawn at 0, 3, 6, 12, 24, and 48 hours and plated in triplicate. Only C. albicans demonstrated any significant growth regardless of fat content. The pH of the admixtures was similar (acidic), and all solutions were hypertonic and found to inhibit bacterial growth. Conclusions suggest that TNA, when formulated with normal concentrations of additives, is no more likely to support growth of contaminant organisms than the traditional solutions. This contradicts the notion that the addition of fat to total parenteral nutrition will enhance the ability of these admixtures to support microbial growth.     

Stability of famotidine 20 and 50 mg/L in total nutrient admixtures

The stability of famotidine in total nutrient admixtures (TNAs) containing dextrose, an intravenous fat emulsion (IVF), and high or low concentrations of amino acids was studied. Famotidine was added to TNA solutions to final concentrations of 20 and 50 mg/L. TNA 1 contained 20% dextrose, IVF 40 g/L, and amino acids 42.5 g/L, and TNA 2 contained 25% dextrose, IVF 25 g/L, and amino acids 21.25 g/L. Control solutions of TNAs 1 and 2 without famotidine were also studied. All solutions were stored at 4 degrees C for 24 hours and then at 20-22 degrees C for 24 hours. The solutions were observed for signs of creaming or coalescence and measured for pH, famotidine concentration, and particle size at 0, 24, and 48 hours. No signs of creaming or coalescence were observed in control or test solutions throughout the study period. Famotidine in TNAs 1 and 2 showed a less than 5% change in concentration over the 48-hour period. Neither time nor amino acid concentration had any significant effect on famotidine concentration. Similarly, there were no significant differences in emulsion particle size between control solutions and TNAs containing famotidine and no significant changes in particle size over time. Famotidine 20 and 50 mg/L is stable in the TNAs tested when stored at 4 degrees C for 24 hours and then at 20-22 degrees C for 24 hours. Famotidine did not appear to disrupt the integrity of the emulsion system.     

Stability of famotidine 20 and 40 mg/L in total nutrient admixtures

The stability of famotidine in two types of total nutrient admixtures (TNAs), one containing 5% intravenous fat emulsion of long-chain triglycerides and the other, of medium- and long-chain triglycerides, was studied. The TNAs, which contained lipids, glucose, amino acids, electrolytes, vitamins, and trace elements, were prepared aseptically in ethylene-vinyl acetate containers. Famotidine 40 mg was added to both types of TNAs and famotidine 80 mg was added to both types to yield concentrations of 20 and 40 mg/L (expressed hereafter as micrograms per milliliter), respectively. A control solution was prepared for each type of TNA. Samples were removed at 0, 12, 24, 48, and 72 hours for measurement of pH and of famotidine concentration by high-performance liquid chromatography; the solutions were visually inspected for color changes, creaming, and formation of precipitates. Particle size distributions were measured at 72 hours and compared with those for the control solutions at time zero. No appreciable changes in pH occurred over 72 hours, and no physicochemical changes were observed. Famotidine 20 and 40 micrograms/mL was stable for at least 72 hours in both types of TNAs. There was no variation in particle size distribution. Famotidine appears to be stable for up to 72 hours at room temperature in the TNAs studied, and it appears not to alter the integrity of the two lipid emulsions.     

Stability of total nutrient admixtures with lipid injectable emulsions in glass versus plastic packaging.

PURPOSE: The physical stability of two emulsions compounded as part of a total nutrient admixture (TNA) was studied in lipids packaged in either glass or plastic containers. METHODS: Five weight-based adult TNA formulations that were designed to meet the full nutritional needs of adults with body weights between 40 and 80 kg were studied. Triplicate preparations of each TNA were assessed over 30 hours at room temperature by applying currently proposed United States Pharmacopeia (USP) criteria for mean droplet diameter, large-diameter tail, and globule-size distribution (GSD) for lipid injectable emulsions. In accordance with conditions set forth in USP chapter 729, the higher levels of volume-weighted percent of fat exceeding 5 microm (PFAT(5)) should not exceed 0.05% of the total lipid concentration. RESULTS: Significant differences were noted among TNA admixtures based on whether the lipid emulsion product was manufactured in glass or plastic. The plastic-contained TNAs failed the proposed USP methods for large-diameter fat globules in all formulations from the outset, and 60% had significant growth in large-diameter fat globules over time. In contrast, glass-contained TNAs were stable throughout and in all cases would have passed proposed USP limits. CONCLUSION: Certain lipid injectable emulsions packaged in plastic containers have baseline abnormal GSD profiles compared with those packaged in glass containers. When used to compound TNAs, the abnormal profile worsens and produces less stable TNAs than those compounded with lipid injectable emulsions packaged in glass containers.     

Growth of bacteria and fungi in total nutrient admixtures

Total nutrient admixtures (TNAs) containing dextrose, amino acids, and fat emulsion were evaluated for their ability to support bacterial and fungal growth. The following solutions were tested: a standard adult total parenteral nutrient (TPN) solution with dextrose, amino acids, and electrolytes, a standard neonatal TPN solution with dextrose, amino acids, and electrolytes, a 10% fat emulsion, a 20% fat emulsion, a TNA with 40% of the total calories as fat, a TNA with 25% of the total calories as fat, a neonatal TNA with 25% of the total calories as fat, a control (fat emulsion was replaced with an equal amount of sterile water) for solution 5, and a control for solution 6. Serial dilutions of each solution were inoculated with 5 X 10(5) bacteria/mL or 5 X 10(3) fungi/mL, incubated, and visually rated on a scale of 0 (no growth) to 4 (maximal growth). Bacterial growth of Pseudomonas aeruginosa, Staphylococcus aureus, Staph. epidermidis, Streptococcus faecalis, and Group JK Corynebacterium was greater in the TNA solutions than in the control or standard TPN solutions. Escherichia coli, Candida tropicalis, and C. albicans grew in all solutions tested. Torulopsis glabrata grew better in solutions that did not contain fat emulsion. Growth characteristics did not differ significantly between the adult and neonatal (more dilute) solutions. The addition of fat emulsion to TPN solutions enhances the ability of these solutions to support bacterial growth; this possibility must be considered when evaluating patients for this type of total parenteral nutrition therapy.     

Practical considerations regarding the use of total nutrient admixtures

The biological concerns, proper storage and administration, and advantages of using total nutrient admixtures (TNAs) for nutritional support are reviewed. In 1983, FDA approved lipid emulsions for administration with dextrose and selected crystalline amino acid preparations (known as three-in-one or total nutrient admixtures). The stability of TNAs is affected by pH, order of mixing, and temperature. Conflicting results have been reported on the issue of microbial growth potential in TNAs. At room temperature, the delivery of the TNA infusate should not exceed 24 hours. Plastic containers that do not contain diethylhexyl phthalate, in sizes up to 3 L, are practical and safe for administration of TNAs. The efficiency of an institution's volumetric pumps should be evaluated before converting to a TNA system because the low final concentrations of lipid emulsion present in the admixtures may render certain pumps inoperable. The practical, nutritional, and potential economic benefits of a TNA delivery system support its use. Further research is needed to determine microbial growth potential, electrolyte and drug compatibilities, and stability under prolonged storage of these admixtures.     

Method for testing the sterility of total nutrient admixtures

A test for determining the sterility of a total nutrient admixture (TNA) containing equal quantities of 10% fat emulsion (Liposyn II), 8.5% amino acids injection, and 50% dextrose injection using the USP membrane filtration procedure was developed and evaluated. Membrane filter selection was determined by analysis of flow rates, membrane fluid compatibility, bubble point stability, and rinse fluid requirements. Microbial challenges employing five organisms (Bacillus subtilis, Escherichia coli, Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa) and both soybean casein digest and fluid thioglycollate media were used to confirm the ability of the test to detect low-level microbial contamination. A polyvinylidene fluoride membrane was determined to be the most appropriate of the membrane types studied because of its superior flow rate and membrane-fluid compatibility. Bubble point testing revealed no detrimental effects on the membrane. The potential problem of haziness caused by retention of the TNA by the membrane with subsequent release in the culture media (which could result in false-positive growth determinations) was diminished by using a sterile 0.1% peptone solution rinse and careful observation techniques. Performance of the sterility test by six hospital pharmacists required an average of 14.2 minutes. Sterility testing of alternate TNAs compounded with Intralipid and Nutralipid was not feasible because of prolonged filtration times. The basic USP membrane filtration procedure for large-volume injections can be used by hospital pharmacists for testing the sterility of TNAs. When fat emulsions are used in compounding, sterility-testing procedures specific to the emulsion product used should be developed and evaluated.     

脂肪乳剂在全营养混合液中的稳定性研究

目的 通过用激光衍射粒度分析仪及结合肉眼观察评价脂肪乳剂在全营养混合液中48h内不同温度下的稳定性。方法 检查洁净室内配制的10个3L袋在48h内乳剂颗粒的大小及混合液稳定性。该混合液在室温（25℃）储存48h、低温（4℃）储存24h后置室温下24h保存，每天用肉眼观察、激光衍射粒度分析仪检查两组样本，并同时测定其pH值。结果 外观观察显示，样本无脂肪乳剂分层或脂肪凝集现象，混合液pH分别为低温组（5．70±0．02）和室温组（5．69±0．01）。激光衍射粒度分析仪测得脂肪颗粒直径在低温组为（0．297±0．0049）μm，室温组为（0．297±0.0047）μm，直径〉0．5μm但〈1．0pm的颗粒〈7％。结论 在室温或低温条件下，48h内脂肪乳剂在全营养混合液中是稳定的。     

Physicochemical stability of highly concentrated total nutrient admixtures for fluid-restricted patients.

PURPOSE: The physicochemical stability of highly concentrated total nutrient admixtures (TNAs) for fluid-restricted patients was studied. METHODS: Five TNAs made from lipid injectable emulsions (50:50 mixture of medium-chain and long-chain triglycerides) designed to meet the full nutritional needs of adults with body weights of 40-80 kg were chosen. Protein was included in the TNAs at 1.5 g/kg for each body weight and was supplied from a concentrated 16% mixture containing the essential and non-essential amino acids. All admixtures were contained in ethylene vinyl acetate bags and were aseptically prepared. Triplicate preparations of each TNA were investigated over 30 hours at room temperature by dynamic light scattering (DLS) and light extinction with single-particle optical sensing (LE-SPOS). RESULTS: No significant changes in the physicochemical stability of the TNAs were observed by DLS (mean droplet size) or LE-SPOS (large-diameter tail) from time 0 (immediately after compounding) to 30 hours. All TNAs met the mean-droplet-size criteria outlined by USP for 20% lipid injectable emulsions. CONCLUSION: Concentrated TNA formulations made from lipid injectable emulsions were stable for 30 hours at room temperature.     

Stability of penicillins in total parenteral nutrient solution

The stability of ticarcillin, mezlocillin, and piperacillin in total parenteral nutrient (TPN) solutions at concentrations commonly used in adults was determined. Each antibiotic was added separately to three different amino acids-dextrose TPN solutions in two concentrations: 10 and 20 mg/mL. Amino acids concentration ranged from 25 g/L to 50 g/L. Dextrose concentration ranged from 100 g/L to 350 g/L. Solutions were assayed for antibiotic concentration immediately after mixing (time 0) and at 4, 8, 24, and 48 hours by high-performance liquid chromatography. The effect of the added penicillins on the stability of amino acids and other TPN additives was not investigated. Mezlocillin and piperacillin 10 and 20 mg/mL exhibited stability in TPN solution at 24 hours. Ticarcillin was stable for 24 hours at a concentration of 10 mg/mL, but at 20 mg/mL it was unstable at all times tested. The three antibiotics demonstrated the same characteristic stability in all three TPN solutions, suggesting that the concentrations of dextrose and amino acids did not affect stability. Ticarcillin, mezlocillin, and piperacillin are stable for 24 hours in the TPN solutions studied.