Parenteral Nutrition Lecture Flashcards
Characteristics of parenteral lipid emulsions
• Particle size: 0.2-0.5 µm; larger size may block
blood capillaries
• All ingredients are purified – Purified oils – Purified emulsifiers (mostly lecithins)
• Isotonic
• High calories in a small volume
• Complies with general requirements of injections
apart from the presence of lipid droplets
History of parenteral lipid emulsions
- First generation lipid emulsions – The oil phase: soybean oil and/or safflower oil, – Rich in polyunsaturated ω-6 fatty acids (PUFA) – Associated with unbalanced fatty acids patterns in cell membranes, leading to:
- modification of the production of lipid mediators (prostaglandings and leukotrienes)
- promotion of immunosuppression and systemic inflammatory reactions
- Second generation lipid emulsions – MCT/LCT (medium/long chain triglycerides)
- Faster clearance from blood stream
- Quicker oxidation and release of energy
- Avoided the side effect on the immune system by ω-6 fatty acids – Olive oil/soybean oil
- More physiological fatty acid patterns
- The immune system is not significantly affected
- Third generation lipid emulsions – The inclusion of fish oil (rich in ω-3 fatty acids) – Designed to achieve certain FA patterns. E.g. SMOFlipid: ω-6 : ω-3 = 2.5:1
How are emulsions used?
• There are two ways of using i.v. fat emulsions:
– Emulsions enter one arm of a Y-connector, and other
solutions enter the other arm, before entering the blood
stream
– Emulsions and all other ingredients are mixed in the same container
• Some common terminologies:
– 2-in-1 solutions: glucose and amino acids are in the same container (emulsions need to be introduced through a Y- connector)
– 3-in-1 solutions, glucose, amino acids and lipid emulsions are all in the same container
– all-in-one solutions
– total nutrient admixtures
An example of admixture: mixing sequence
• Intralipid has been shown to be compatible with either
Novamine® or 8.5% Travasol® or 10% Travasol®
• Mixing sequence (must use strict aseptic techniques):
– Dextrose should be added to the container first, followed by amino acids, and Intralipid® should be added last; with gentle shaking during the process. Or,
– All added together and shake gently.
– Note: Dextrose injection is acidic (pH 3.5-6.5). Avoid localised concentration effect.
• Storage: 2-8°C. <24hours. Do not freeze. What if
frozen?
In vivo fate of emulsions after i.v. injection
• Lypolysis mediated by apolipoproteins (e.g. Apo CII,
which facilitates lipolysis by activating lipoprotein
lypase). The droplets are treated as naturally occurring
lipids such as chylomicrons
• Removal by the body’s defence systems: mononuclear phagocyte systems (MPG) /reticuloendothelial systems (RES). The emulsion droplets will end up mainly in the liver, spleen and lung
Factors affecting the in vivo fate of emulsions
• Droplet size – a reduction in droplet size reduces the
uptake by the liver and increases the circulation time in
the blood. Vice versa.
• The emulsifier layer on droplets surface.
– Long hydrophilic chains, such as PEG, reduce the
adsorption of protein, and consequently lead to the
increase of circulation time in in the blood
– Sphingomyelin also increases the circulation time of
emulsions in vivo
• The oil phase
– cholesterol oleate reduced the clearance of droplets from the blood circulation according to some studies
Stability issues of parenteral emulsions in nutrient admixtures
• Potential oxidation of lipids
• Precipitation: Calcium. Could the detection be
made more difficult by the existence of fat emulsions?
• The addition of electrolytes: Na+, Ca2+ etc – Lipid emulsions are generally sensitive to electrolytes
(diffuse double layer compressed, zeta potential reduced)
• The addition of amino acids: pKa and charges?
• The addition of vitamins
Compatibility/stability assessments of
total nutrient admixtures
What can be seen by the naked eye? – Change of colour – Creaming – Breaking (phase separation) – Precipitation? • Particle size: what are the size limits? – Microscopy – Single particle optical counting – Electrical zone sensing – Laser diffraction – Photon correlation spectroscopy (PCS) • Microbial growth • Zeta potential analysis • Simulation of conditions of clinical use
USP <729> - Droplet size distribution in lipid injectable emulsions
• Mean diameter of oil droplets : use one of the following
two:
– Classical light scattering, based on Mie scattering theory (also called Laser Diffraction) – Dynamic light scattering (DLS), also known as photon correlation spectroscopy (PCS)
• Measurement of large globule content
– Light obscuration or extinction (e.g. AccuSizer)
• Requirements:
– Intensity-weighted mean droplet diameter (MDD) must be <500nm
– PFAT5 (the volume-weighted lipids reside in oil droplets greater than 5µm) must be smaller than 0.05%
Advantages of using parenteral emulsions as drug carriers
• Solubilisation of low solubility drugs,
• e.g. diazepam, vitamin A, vitamin E and propofol
• Reduction of side effects, including irritation, pain
and toxicity
• Possible site-specific drug delivery
• Stabilisation of drugs that are sensitive to hydrolysis
• Potential for sustained release
Retention of drug in oil droplets
• If the drug remains within the droplets after injection, it will move with the droplets and its distribution within the body will be similar to the droplets
• If the drug releases into the plasma quickly after
injection, then the in vivo fate will likely be different to the emulsion droplets
• Drugs with logP (n-octanol/water) > 9 would be able to stay in the droplets after injection into the body
Long circulating emulsions
• If drug is removed too fast from the blood circulation, it may not reach the desired site of action. Instead, it may end up in the RES-rich organs (e.g. the liver).
• The coating of the droplet surface with PEG-containing
emulsifiers will reduce the adsorption of proteins and
hence avoid the body’s elimination mechanisms. Therefore, the circulation time is increased
• Emulsifiers often used – PEG-phospholipids: a PEG chain is attached to the phospholipids, e.g. PEG-PE – Poloxamer: triblock co-polymers with PEG chains.
Stability considerations
- The addition of drugs usually add stress to the stability of an emulsion. So extra stabilisers may be needed, e.g. sodium oleate, sodium deoxycholate etc.
- Drug may release into the aqueous phase and crystallise
- Preservatives may need to be included to inhibit microbial growth upon unintended contamination during use (the emulsion is a very good media for microbial growth)
Stability assessments
• Visual examination – Creaming, flocculation, change of colour etc. • Potential crystallisation of drug • Particle size measurement • Zeta potential measurement • Sterility • pH • Preservative test • Sterility test • Pyrogen • Chemical analysis (oxidation, hydrolysis of lipids)
To provide 1200 kcal energy to a patient from a
2000 mL glucose solution, what should be the
concentration of the solution?
1200/4/2000=0.15=15% w/v
