brief review on 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

11. 01/03/16 11

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

22. 01/03/16 22

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

24. Marketed Products
01/03/16 24

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

26. THANK YOU.
01/03/16 26