Lipid emulsions in clinical nutrition: Enteral and parenteral nutrition.

Clinical nutrition emulsions are important products that can be life-saving for many patients suffering from gastrointestinal tract disorders, swallowing impairment, cancer, liver diseases, and many other clinical conditions. The transfer of lipids to the human body can be either intravenously (Parenteral Nutrition, PN) or through the gastrointestinal tract (Enteral Nutrition, EN). PN emulsions are considered pharmaceuticals and thus regulated accordingly. On the other hand, EN emulsions are classified as Food for Specific Medical Purposes (FSMP) and do not follow pharmaceutical regulations. Regarding product design, PN emulsions must follow theoretical emulsion formulation and production aspects, but special requirements regarding droplet size distribution must be followed to comply with national pharmacopeia monographs. Furthermore, a full clinical program on clinical evidence to prove safety and efficacy must be provided for marketing approval. On the contrary, EN emulsions require limited clinical evidence to substantiate health or clinical benefits. A short introduction to clinical nutrition with a focus on lipid emulsions is presented in this chapter. Furthermore, a general overview of the composition and main ingredients of clinical nutrition lipid emulsions is reviewed. Main clinical aspects are also mentioned here, highlighting the difficulties of clinically proving the efficacy of these products. The manufacturing and control of clinical nutrition emulsions are also reviewed, focusing on PN products and the main regulatory requirements related to the safety of these intravenous emulsions. Finally, stability and physicochemical properties are reviewed, and examples of commercially available products are used to illustrate these properties linked to the stability of these products. Lipids in clinical nutrition is a moving field and we do hope this chapter may remain a valuable source to understand newly emerging research on this topic.

Kinetics of Egg-Yolk Protein Hydrolysis and Properties of Hydrolysates.

Lecithin-free egg yolk (LFEY) is a byproduct of the extraction of egg-yolk phospholipids, which contain approximately 46% egg yolk proteins (EYPs) and 48% lipids. The enzymatic proteolysis is the alternative to increase the commercial value of LFEY. The kinetics of proteolysis in full-fat and defatted LFEY with Alcalase 2.4 L was analyzed in terms of the Weibull and Michaelis-Menten models. A product inhibition effect was also studied in the full-fat and defatted substrate hydrolysis. The molecular weight profile of hydrolysates was analyzed by gel filtration chromatography. Results pointed out that the defatting process did not importantly affect the maximum degree of hydrolysis (DHmax) in the reaction but rather the time at which DHmax is attained. The maximum rate of hydrolysis (Vmax) and the Michaelis-Menten constant KM were higher in the hydrolysis of the defatted LFEY. The defatting process might have induced conformational changes in the EYP molecules, and this affected their interaction with the enzyme. Consequently, the enzymatic reaction mechanism of hydrolysis and the molecular weight profile of peptides were influenced by defatting. A product inhibition effect was observed when adding 1% hydrolysates containing peptides lower than 3 kDa at the beginning of the reaction with both substrates.

High-pressure pulses for Aspergillus niger spore inactivation in a model pharmaceutical lipid emulsion.

High hydrostatic pressure (HHP) is a non-thermal process widely used in the food industry to reduce microbial populations. However, rarely its effect has been assessed in products with high oil content. This study evaluated the efficacy of HHP (200, 250, and 300 MPa) at different temperatures (25, 35, and 45 °C) by cycles (1, 2, or 3) of 10 min in the inactivation of Aspergillus niger spores in a lipid emulsion. After treatments at 300 MPa for 1 cycle at 35 or 45 °C, no surviving spores were recovered. All treatments were modeled by the linear and Weibull models. The presence of shoulders and tails in the treatments at 300 MPa at 35 or 45 °C resulted in sigmoidal curves which cannot be described by the linear model, hence the Weibull + Tail, Shoulder + Log-lin + Tail, and double Weibull models were evaluated to elucidate the inactivation kinetics. The tailing formation could be related to the presence of resistance subpopulations. The double Weibull model showed better goodness of fit (RMSE <0.2) to describe the inactivation kinetics of the treatments with the higher spore reductions. HHP at 200-300 MPa and 25 °C did not reduce the Aspergillus niger spores. The combined HHP and mild temperatures (35-45 °C) favored fungal spore inactivation. Spore inactivation in lipid emulsions by HHP did not follow a linear inactivation. HHP at mild temperatures is an alternative to the thermal process in lipid emulsions.

Rheological Issues on Oropharyngeal Dysphagia.

There is an increasing proof of the relevance of rheology on the design of fluids for the diagnosis and management of dysphagia. In this sense, different authors have reported clinical evidence that support the conclusion that an increase in bolus viscosity reduces the risks of airway penetration during swallowing. However, this clinical evidence has not been associated yet to the definition of objective viscosity levels that may help to predict a safe swallowing process. In addition, more recent reports highlight the potential contribution of bolus extensional viscosity, as elongational flows also develops during the swallowing process. Based on this background, the aim of this review paper is to introduce the lecturer (experts in Dysphagia) into the relevance of Rheology for the diagnosis and management of oropharyngeal dysphagia (OD). In this sense, this paper starts with the definition of some basic concepts on Rheology, complemented by a more extended vision on the concepts of shear viscosity and elongational viscosity. This is followed by a short overview of shear and elongational rheometrical techniques relevant for the characterization of dysphagia-oriented fluids, and, finally, an in-depth analysis of the current knowledge concerning the role of shear and elongational viscosities in the diagnosis and management of OD (shear and elongational behaviors of different categories of dysphagia-oriented products and contrast fluids for dysphagia assessment, as well as the relevance of saliva influence on bolus rheological behavior during the swallowing process).

Development of an in vitro distal gastric simulator to mimic the mechanical action of the human stomach.

This work describes the development of an in vitro distal gastric simulator (IV-DGS), where the distal region of the human stomach was replicated. Soft membranes were fabricated to simulate the gastric walls to generate a mechanical condition close to the physiological behavior. An esophageal manometry catheter was used to record the pressure amplitude values and the pressure waveform from the contractile activity. Three different experiments, considering the conditions of the fed state, were carried out to evaluate the performance of the proposed simulator. The first one was related to the evaluation of the mixing capability by dissolving methylene blue in distilled water and aqueous solutions of guar gum.The second one was focused on evaluating the acidification rate of milk with hydrochloric acid (HCl). Finally, food disintegration was evaluated using sausage and melon as meals. The IV-DGS demonstrated the capability to reproduce a pressure range between 15 and 30 mmHg, and the waveform reproduced the propulsion and retropulsion flows which were consistent with in vivo experiments reported elsewhere (Maqbool et al., 2009). The IV-DGS produced about 75 % disintegration of the pounded sausage, which represents an improvement of more than 200 % and 35 % compared to the results obtained using the static arrays without and with agitation, respectively. These experiments demonstrated how important the mechanical dynamic conditions are to promote the chemical and mechanical reaction during in vitro digestion simulations.

Advances in 3D printing of food and nutritional products.

The main advantage of both 3D printing (3DP) and 3D food printing (3DFP) over other technologies is the enormous capacity of both techniques for customization. Its use makes it possible to obtain products without planning and implementing a complex and costly manufacturing process. This makes 3DFP a technology of choice for the preparation of food products that meet specific needs, such as controlled nutritional or rheological properties. However, further technological developments are still needed before 3DFP can be considered fully useful for innovative and demanding applications. If both preparation and post-processing of materials based on 3D printing are optimized, aiming to reduce production time and/or complication for non-expert users, this would open a whole new range of possibilities. It is in this sense that the development of advanced 3DFP systems becomes a must. This chapter reviews current advances in extrusion-based 3D food printing systems, with in situ gelation and mixing as key aspects to better exploit the potential of 3DFP. On one hand, 3DFP systems based on in situ gelation (G3DFP) provide greater control over the final properties of the printed products, as the selection of adequate printing parameters gives the possibility of influencing the gelation process. On the other hand, mixing is indispensable for true 3DFP automation, so that the formulations do not have to be prepared by the user. Different innovative 3DFP systems based on gelling and/or mixing are presented in this chapter. Finally, the status and future of extrusion-based 3DFP, and its application in the production of customized foods for specific needs, are also overviewed.

Comprehensive profiling of conjugated fatty acid isomers and their lipid oxidation products by two-dimensional chiral RP×RP liquid chromatography hyphenated to UV- and SWATH-MS-detection.

This research reports on the development of a comprehensive two-dimensional liquid chromatography (2D-LC) method hyphenated to inline DAD-UV and ESI-QTOF-MS/MS-detection for the separation of conjugated polyunsaturated fatty acid isomers and structurally related (saturated, unconjugated, oxidized) compounds. In pharmaceutical lipid formulations conjugated fatty acids can be found as impurities, generated by oxidation of polyunsaturated fatty acids. Due to the structural complexity of resultant multi-component samples one dimensional liquid chromatography may be suboptimal for quality control and impurity profiling. The screened reversed-phase columns showed a lack of selectivity for the conjugated fatty acid isomers but the resolutions improved with the shape selectivity of the stationary phases (C18- < C30- < cholesteryl-ether-bonded). Further enhanced selectivity for the non-chiral conjugated FAs could be achieved with amylose/cellulose-based chiral stationary phases (CSPs) which harbor cavities for selective inclusion depending on E/Z configurations of the double bonds of the analytes. Amylose-based CSPs showed higher selectivity for conjugated fatty acids than the cellulose-based polysaccharide CSPs. Hyphenating the chiral and reversed-phase columns in a comprehensive 2D-LC-setup was favorable since they showed orthogonality and good compatibility, because both were operated under RP-conditions. The chiral dimension (1D) mainly separated the different isomers, while the reversed-phase dimension (2D) separated according to number of double bonds and degree of oxidation. Using this setup, advanced structural annotation of unknowns was possible based on UV-, MS1- and MS2-spectra. Data-independent acquisition (by SWATH) enabled differentiation of positional isomers of oxidized lipids by characteristic MS2-fragments and elucidation of co-eluted compounds by selective extracted ion chromatograms of fragment ions (MS2 EICs).

Combination of supercritical CO2 and high-power ultrasound for the inactivation of fungal and bacterial spores in lipid emulsions.

For the first time, this study addresses the intensification of supercritical carbon dioxide (SC-CO2) treatments using high-power ultrasound (HPU) for the inactivation of fungal (Aspergillus niger) and bacterial (Clostridium butyricum) spores in oil-in-water emulsions. The inactivation kinetics were analyzed at different pressures (100, 350 and 550 bar) and temperatures (50, 60, 70, 80, 85 °C), depending on the microorganism, and compared to the conventional thermal treatment. The inactivation kinetics were satisfactorily described using the Weibull model. Experimental results showed that SC-CO2 enhanced the inactivation level of both spores when compared to thermal treatments. Bacterial spores (C.butyricum) were found to be more resistant to SC-CO2 + HPU, than fungal (A.niger) ones, as also observed in the thermal and SC-CO2 treatments. The application of HPU intensified the SC-CO2 inactivation of C.butyricum spores, e.g. shortening the total inactivation time from 10 to 3 min at 85 °C. However, HPU did not affect the SC-CO2 inactivation of A.niger spores. The study into the effect of a combined SC-CO2 + HPU treatment has to be necessarily extended to other fungal and bacterial spores, and future studies should elucidate the impact of HPU application on the emulsion's stability.

Effect of operating parameters on the physical and chemical stability of an oil gelled-in-water emulsified curcumin delivery system.

BACKGROUND: Curcumin is a natural antioxidant with important beneficial properties for health, although its low bioavailability and sensitivity to many environmental agents limits its use in the food industry. Furthermore, some studies mention a potential synergistic effect with omega-3 polyunsaturated fatty acids, comprising other bioactive compounds extremely unstable and susceptible to oxidation. A relatively novel strategy to avoid oxidation processes is to transform liquid oils into three-dimensional structures by adding a gelling agent and forming a self-assembled network that can later be vectorized by incorporating it into other systems. The present study aimed to design and optimize an oil gelled-in-water curcumin-loaded emulsion to maximize curcumin stability and minimize lipid oxidation in terms of some critical operating parameters, such as dispersed phase, emulsifier and stabilizer concentrations, and homogenization rate. RESULTS: The operating conditions that had a significant effect on the formulation were the dispersed phase weight fraction affecting droplet size and total lipid oxidation, homogenization conditions affecting droplet size and primary lipid oxidation, and emulsifier concentration affecting droplet size (significance level = 95%). The optimal formulation for maximizing curcumin load and minimizing lipid oxidation in the oleogelified matrix was 140.4 g kg-1 dispersed phase, 50.0 g kg-1 emulsifier, 4.9 g kg-1 stabilizer and homogenization speed 1016 × g. CONCLUSION: The results obtained in the present study provide a valuable tool for the rational design and development of oil gelled-in-water emulsions that stabilize and transport bioactive compounds such as curcumin. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Freeze-drying: A relevant unit operation in the manufacture of foods, nutritional products, and pharmaceuticals.

Freeze-drying, a drying unit operation frequently used in food, pharmaceutical, and biopharmaceutical industries to prolong the shelf life of labile products, is an energy-intensive, time-consuming, and expensive process. Although all three steps (freezing, primary drying, and secondary drying) of freeze-drying are important, primary drying is the longest and most critical one. As sublimation during primary drying is mainly described in terms of heat and mass transfer, the present work provides extensive theoretical and experimental analyses of these processes. First, a detailed review of the current state-of-the art of freeze-drying, focusing on the drying stage, is given, which contributes to a fundamental understanding of the drying process. Second, a detailed experimental study of the drying section of the freeze-drying process is discussed, furnishing information on the relationship between input and output process parameters during the primary drying stage and thus aiding freeze-drying process design and optimization. In this regard, the influence of primary drying input parameters (i.e., shelf temperature and chamber pressure) and vial position on output parameters such as product temperature, sublimation rate, overall vial heat transfer coefficient, and resistance to mass transfer of the dried product are extensively discussed. For all combinations of shelf temperature and chamber pressure studied herein, the highest product temperature, sublimation rate, and overall vial heat transfer coefficient are observed in front edge vials, whereas the lowest values are observed in center vials. In general, the highest sublimation rate, at a given product temperature, is observed for low chamber pressure-high shelf temperature combinations.

Therapeutic Effect, Rheological Properties and α-Amylase Resistance of a New Mixed Starch and Xanthan Gum Thickener on Four Different Phenotypes of Patients with Oropharyngeal Dysphagia.

Thickened fluids are a therapeutic strategy for oropharyngeal dysphagia (OD). However, its therapeutic effect among different phenotypes of OD patients has not yet been compared. We aimed to assess the therapeutic effect and α-amylase resistance of a mixed gum/starch thickener [Fresubin Clear Thickener® (FCT)] on four phenotypes of OD patients: G1) 36 older; G2) 31 head/neck cancer (HNC); G3) 30 Parkinson's disease; and G4) 31 chronic post-stroke. Therapeutic effect of FCT was assessed during videofluoroscopy using the Penetration-Aspiration Scale (PAS), for 5/20 mL boluses, at four levels of shear-viscosity (<50, 250, 1000 and 2000 mPa·s). The effect of α-amylase was assessed after 30 s of oral incubation. Patients had high prevalence of VFS signs of impaired efficacy (98.44%) and safety (70.31%) of swallow with a severe PAS score (4.44 ± 0.20). Most severe OD was in HNC (80.6% unsafe swallows). FCT showed a strong therapeutic effect on the safety of swallow at a range between 250-1000 mPa·s (74.19-96.67%, safe swallows in G1, G3, G4, and 58.06% in G2), without increasing pharyngeal residue. Viscosity was unaffected by α-amylase. Increasing shear-viscosity with FCT causes a strong viscosity-dependent therapeutic effect on the safety of swallow. This effect depends on the phenotype and is similar among older, Parkinson's and post-stroke patients.

Non-thermal pasteurization of lipid emulsions by combined supercritical carbon dioxide and high-power ultrasound treatment.

Supercritical carbon dioxide (SC-CO2) is a novel method for food pasteurization, but there is still room for improvement in terms of the process shortening and its use in products with high oil content. This study addressed the effect of high power ultrasound (HPU) on the intensification of the SC-CO2 inactivation of E. coli and B. diminuta in soybean oil-in-water emulsions. Inactivation kinetics were obtained at different pressures (100 and 350 bar), temperatures (35 and 50 °C) and oil contents (0, 10, 20 and 30%) and were satisfactorily described using the Weibull model. The experimental results showed that for SC-CO2 treatments, the higher the pressure or the temperature, the higher the level of inactivation. Ultrasound greatly intensified the inactivation capacity of SC-CO2, shortening the process time by approximately 1 order of magnitude (from 50 to 90 min to 5-10 min depending on the microorganism and process conditions). Pressure and temperature also had a significant (p < 0.05) effect on SC-CO2 + HPU inactivation for both bacteria, although the effect was less intense than in the SC-CO2 treatments. E. coli was found to be more resistant than B. diminuta in SC-CO2 treatments, while no differences were found when HPU was applied. HPU decreased the protective effect of oil in the inactivation and similar microbial reductions were obtained regardless of the oil content in the emulsion. Therefore, HPU intensification of SC-CO2 treatments is a promising alternative to the thermal pasteurization of lipid emulsions with heat sensitive compounds.

Use of a temperature ramp approach (TRA) to design an optimum and robust freeze-drying process for pharmaceutical formulations.

Freeze-drying, until now, has been a process that was designed using a trial and error experimental approach. This approach is often material and time consuming, and the resulting freeze-drying processes are neither optimum nor robust. Accordingly, the objective of this study was to develop a simple-to-use and experimental-based approach to design an optimum and robust freeze-drying process for any given formulation. The temperature ramp approach (TRA) detailed in this study involves the implementation of a customized design of experiments (DoE) to perform few (three or four) experiments using a given drug formulation. The DoE results are analyzed to define optimum processing conditions (i.e., shelf temperature and chamber pressure) based on a predefined range of target product temperature for primary drying, which could be defined from formulation characterization at its frozen state. In this study, a successful freeze-drying process of two model formulations using the TRA was designed. Verification experiments at the optimum processing conditions showed excellent agreement in both product temperature and sublimation rate with the values obtained using the TRA. Thus, the TRA detailed in this study offers a significant advantage to reduce development time and material, and enhance the efficiency and robustness of the resulting freeze-drying process.

An Experimental-Based Approach to Construct the Process Design Space of a Freeze-Drying Process: An Effective Tool to Design an Optimum and Robust Freeze-Drying Process for Pharmaceuticals.

The application of quality by design (QbD) is becoming an integral part of the formulation and process development for pharmaceutical products. An essential feature of the QbD philosophy is the design space. In this sense, a new approach to construct a process design space (PDS) for the primary drying section of a freeze-drying process is addressed in this paper. An effective customized design of experiments (DoE) is developed for freeze-drying experiments. The results obtained from the DoE are then used to construct the product-based PDS. The proposed product-based PDS construction approach has several advantages, including (1) eliminating assumptions on the heat transfer coefficient and dried product resistance, as it is constructed from experimental results specifically obtained from a given formulation, yielding more realistic and reliable results and (2) PDS construction based on a narrow range of product temperatures and considering the variations in product temperature and sublimation rate of vials across a shelf. This guarantees the effectiveness and robustness of the process and facilitates the process scale-up and transfer. The PDS developed herein was experimentally verified. The PDS predicted parameters were in excellent agreement with the experimentally obtained parameters.

The Importance of Understanding the Freezing Step and Its Impact on Freeze-Drying Process Performance.

The freeze-drying process is a combination of 2 equally important processes, freezing, and drying. In the past, the effort was mainly focused on optimizing the drying process without considering the possible effects of the freezing step. During freezing, a solution undergoes several physical changes, including a supercooling state. The degree of supercooling of a solution dictates the ice habit (size, number, and morphology) during freezing, which impacts the subsequent drying process, such as the resistance to water vapor flow. Therefore, heterogeneous degree of supercooling leads to heterogeneous ice habits and, in turn, to heterogeneous drying behavior. This poses significant challenges during freeze-drying process development, optimization, and scale up. Hence, controlling the degree of supercooling significantly improves freeze-drying process design. The aim of the current review is to gather existing information on the physicochemical phenomena involved in the freezing process and how these phenomena impact the subsequent drying step of the freeze-drying process. In addition, modification of the freezing process and different techniques used to actively control the degree of supercooling during freezing will be reviewed and discussed. Their impact on freeze-drying process performance will be also addressed.

Building a three-dimensional model of the upper gastrointestinal tract for computer simulations of swallowing.

We aimed to provide realistic three-dimensional (3D) models to be used in numerical simulations of peristaltic flow in patients exhibiting difficulty in swallowing, also known as dysphagia. To this end, a 3D model of the upper gastrointestinal tract was built from the color cryosection images of the Visible Human Project dataset. Regional color heterogeneities were corrected by centering local histograms of the image difference between slices. A voxel-based model was generated by stacking contours from the color images. A triangle mesh was built, smoothed and simplified. Visualization tools were developed for browsing the model at different stages and for virtual endoscopy navigation. As result, a computer model of the esophagus and the stomach was obtained, mainly for modeling swallowing disorders. A central-axis curve was also obtained for virtual navigation and to replicate conditions relevant to swallowing disorders modeling. We show renderings of the model and discuss its use for simulating swallowing as a function of bolus rheological properties. The information obtained from simulation studies with our model could be useful for physicians in selecting the correct nutritional emulsions for patients with dysphagia.

Droplet-size distribution and stability of commercial injectable lipid emulsions containing fish oil.

PURPOSE: The droplet size of commercial fish oil-containing injectable lipid emulsions, including conformance to United States Pharmacopeia (USP) standards on fat-globule size, was investigated. METHODS: A total of 18 batches of three multichamber parenteral products containing the emulsion SMOFlipid as a component were analyzed. Samples from multiple lots of the products were evaluated to determine compliance with standards on the volume-weighted percentage of fat exceeding 0.05% (PFAT(5)) specified in USP chapter 729 to ensure the physical stability of i.v. lipid emulsions. The products were also analyzed to determine the effects of various storage times (3, 6, 9, and 12 months) and storage temperatures (25, 30, and 40 °C) on product stability. Larger-size lipid particles were quantified via single-particle optical sensing (SPOS). The emulsion's droplet-size distribution was determined via laser light scattering. RESULTS: SPOS and light-scattering analysis demonstrated mean PFAT(5) values well below USP-specified globule-size limits for all the tested products under all study conditions. In addition, emulsion aging at any storage temperature in the range studied did not result in a significant increase of PFAT(5) values, and mean droplet-size values did not change significantly during storage of up to 12 months at temperatures of 25-40 °C. CONCLUSION: PFAT(5) values were below the USP upper limits in SMOFlipid samples from multiple lots of three multichamber products after up to 12 months of storage at 25 or 30 °C or 6 months of storage at 40 °C.