Parenteral emulsions
- 1. 01/03/16 1 Presented by- Sulabh Singhania M.Pharm – 1st SEM PARENTERAL EMULSIONS Enrollment No-201504100410019 DEPARTMENT OF PHARMACEUTICS
- 2. INTRODUCTION - Emulsions • An emulsion is a dispersion of a liquid as globules in another liquid that is immiscible with the first. • Out of the two participating liquids in dispersion system one is water and the other is oil. • Broadly emulsions are of following types: a) O/W - oil dispersed in water. b) W/O - water dispersed in oil. c) W/O/W -multiple emulsions • As the two liquids are immiscible with one another a third component is added to stabilize the system and it is known as emulsifiers ( emulgent/ emulsifying agent) 01/03/16 2
- 3. Schematic representation of emulsions 01/03/16 3
- 4. Parenteral Emulsions(PE) • Same definition of emulsions can be put forth to parenteral context with droplet size ranging 0.1-5 µm in diameter, with a stringent sterility control. • Parenteral emulsion are also of two types o/w and w/o but the later is not being used much. • Initially PE were developed to serve as an intravenous source of both calories and essential fatty acids. • Later it evolved as a promising delivery system for lipophilic substances. • Types of Parenteral Emulsions W/O emulsion (S.C.). O/W Sustained release depot preparation (I.M.). O/W nutrient emulsion (I.V.) 01/03/16 4
- 5. Advantages of PE • Reduction in pain, irritation, and thrombophlebitis diazepam (Valium®/Assival®; Vehicle, propylene glycol). Diazepam emulsion (Diazemuls®) • Reduced Toxicity Cyclosporine –had dose dependent nephrotoxicity , emulsion have less effect on GFR • Improved Stability and Solubility clarithromycin, all-trans-retinoic acid, sodium phenobarbital, • Targeted Drug delivery Wistar rats wherein emulsion pre-loaded with rec-apoE was taken up to a greater extent(70% of the injected dose) by the liver compared with the control formulation without apoE (30% of the injected dose) 01/03/16 5
- 6. Advantages of PE contd.. 01/03/16 6
- 7. Disadvantages of PE • LCT and MCT approved by the regulatory agencies are not necessarily good solvents of lipophilic drugs. • Even if the drug shows reasonable solubility in the oil phase, the oil phase in the emulsion system generally does not exceed 30% causing drug- loading challenges for drugs with high dose requirements. Development of novel oils with improved drug solubility would require extensive toxicity studies. • Incorporated drugs may render the emulsion physically unstable during storage making formulation efforts challenging. There are strict regulatory requirements with respect to the control of droplet size of injectable emulsions. • Limited number of approved safe emulsifiers. 01/03/16 7
- 8. INJECTABLE EMULSION COMPONENTS • Lipids(oily phase) LCTs-triolein, soybean oil, safflower oil, sesame oil, and castor oil MCTs- fractionated coconut oil SCTs-tributyrin Vitamin E and other approved lipids • Emulsifiers Natural lecithin , polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), Pluronic® F68 and many more. • Aqueous phase(w.f.i) tonicity modifiers-glycerin, sorbitol, or Xylitol pH adjustment- NaOH to (-pH-8) • Antioxidants such as α-tocopherol, ascorbic acid, and deferoxamine mesylate. 01/03/16 8
- 9. INJECTABLE EMULSION COMPONENTS contd….• Antimicrobials sodium benzoate and benzyl alcohol. • Tonicity modifier (280–300 mOsm kg-1 ) Glycerol, sorbitol, xylitol Manufacturing Formulation • Water soluble and oil-soluble ingredients are generally dissolved in the aqueous phase and oil phase, respectively. • Emulsifiers, such as phosphatides, can be dispersed in either oil or aqueous phase. • The lipid phase is then generally added to the aqueous phase under controlled temperature and agitation (using high-shear mixers) to form a homogenously dispersed coarse emulsion. 01/03/16 9
- 10. Manufacturing contd… • The coarse emulsion is then homogenized (using a micro fluidizer or a high-pressure homogenizer) at optimized pressure, temperature and number of cycles to further reduce the droplet size and form fine emulsion. • The pH of the resulting fine emulsion is then adjusted to the desired value and the emulsion is filtered through 1–5 μm filters. 01/03/16 10
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- 12. Drug Incorporation Methods • de novo method- prior to emulsification • Extemporaneous addition- after emulsification • SolEmuls® Technology- solvent free technology has been developed that localizes the drug at the interface of the emulsion. In this approach, the drug, as ultra-fine powders/nanocrystals, is added to preformed emulsions (e.g., Lipofundin® and Intralipid®) or to coarse emulsions, and the mixture is then homogenized until the drug crystals are dissolved, resulting in localization of drug at the interface. • Drugs that are slightly soluble in oil can be incorporated into the emulsions with the aid of co-solvents . The solvents are evaporated during the manufacturing process. 01/03/16 12
- 13. Drug Incorporation Methods contd… • Another approach involves dissolving drug and phospholipids in organic solvents followed by evaporation of the organic phase under reduced pressure in round bottom flasks to form a thin film. Upon sonication with the aqueous phase, a liposome-like dispersion is formed. Addition of the oil phase to this drug liposome dispersion followed by emulsification results in an emulsion formulation. A schematic depicting drug distribution within the emulsion system 01/03/16 13
- 14. STERLIZATION • Sterilization of the formulations can be achieved by terminal heat sterilization or by aseptic filtration. • Terminal sterilization generally provides greater assurance of sterility of the final product. • However, if the components of the emulsions are heat labile sterile filtration can be used. Sterilization by filtration requires the emulsion droplet size to be below 200 nm 01/03/16 14
- 15. Considerations In The Development of Parenteral Emulsions • Globule size Strict globule size requirement, maximum globule size should be less than 2µm. Sizes more than this has a direct effect on both toxicity and stability. • Surface charge(zeta potential) A reduction in the electrical charge is known to increase the rate of flocculation and coalescence, and thus the measurement of surface charge is useful in stability assessments • Oils Purity is critical for any oil employed in parenteral products. Extensive purification must be performed to remove undesirable components such as peroxides, pigments, thermal and oxidative decomposition products, and certain unsaponifiable matter. 01/03/16 15
- 16. Considerations In The Development of Parenteral Emulsions contd.. • Oils • Emulsifiers 01/03/16 16
- 17. Considerations In The Development of Parenteral Emulsions contd.. • pH – buffering agents are not typically added because there is the potential for buffer catalysis of the hydrolysis of lipids. Alternatively, the pH is adjusted with a small quantity of sodium hydroxide. – The optimum pH of the finished emulsion is in the general range of 6–7 – Initially, this pH range allows for the ionization of the phosphate groups at the surface of the lecithin film, leading to an optimum surface charge for the globules – Low pH(values lower than 5) should be avoided as the electrostatic repulsion between emulsified oil globules is decreased, resulting in increased globule size and coalescence – the second benefit of this pH range is minimized lecithin hydrolysis. 01/03/16 17
- 18. Considerations In The Development of Parenteral Emulsions contd.. • Rate of addition: coarse emulsion ‘dispersion’ preparation – The rate of addition of the oil phase to the aqueous phase should be controlled and optimized. – If the rate of addition is too rapid, incomplete dispersion of the oil into the aqueous phase can occur. – The optimum size is formulation-specific, but it could be less than 20 µm for the ‘coarse emulsion’ phase. • Temperature • Homogenization and globule size reduction – Once the coarse emulsion is formed, it is necessary to reduce the globule size even further by homogenization 01/03/16 18
- 19. CHARACTERIZATION OF INJECTABLE EMULSIONS • Droplet Size Optical microscopy, atomic force microscopy and electron microscopy. • Zeta Potential (the electrical potential at the shear plane) A zeta potential value of ±25 mV has been suggested to produce a stable emulsion. • Viscosity depends on a number of factors such as surfactants and oils used, ratio of dispersed and continuous phase, droplet size distribution and other factors. It should be optimum • pH pH of these lipid emulsions decrease during sterilization and storage as a result of increase in FFA content due to the hydrolysis, will alter zeta potential and affect the stability. • In vitro release dialysis bag method, diffusion cell method, centrifugal ultrafiltration .01/03/16 19
- 20. A full characterization should include: • physical examination: visual observation for creaming, coalescence, oil separation, and color change; • chemical analysis: –determination and characterization of the drug substance, oil, emulsifier(s) and adjuvants present –degradation of related substances, including in particular- free fatty acids, lysolecithin and oxidative degradation products; • pH determination; • globule size and surface charge; • preservative test; • sterility test- Membrane filtration and Direct inoculation • pyrogen test- LAL test, rabbit test. 01/03/16 20
- 21. Stability testing of emulsions 01/03/16 21
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- 23. Packaging of Parenteral Emulsions • Parenteral emulsions provided in volumes of 100 to 1000 ml are packaged in USP type I & II Glass bottles • Siliconized Bottles with hydrophobic inner surface can be used • Rubber closures are most commonly used. • Closures must not be permeable to oxygen or become softened by contact with the oil phase of emulsion. 01/03/16 23
- 25. Reference's • Ketan Hippalgaonkar, Soumyajit Majumdar, and Viral Kansara. Injectable Lipid Emulsions—Advancements, Opportunities and Challenges • Alison G. Floyd’s Top ten considerations in the development of parenteral emulsions 01/03/16 25