Phospholipids in Mixed Micelles

Phospholipids in Parenteral Applications

 Phospholipids in Intravenous Delivery Vehicles

Lipid Emulsion (O/W) Liposome Mixed Micelle

150 – 350 nm 20 – 10,000 nm 5 – 10 nm

Lipophilic Drug

Hydrophilic Drug

Bile Salt

Diacyl PL (PC)

Fatty Acids
 Properties and Benefits – Mixed Micelles

• Technology applied by Roche for diazepam (i.v.) and vitamin K solubilization

(i.v. and oral)

• Replacement of organic solvents in injections and avoidance of solvents in

production processes and formulations

• Comprises an approximately equimolar mixture of soybean

phosphatidylcholine (SPC) and sodium glycocholate or sodium deoxycholate

• Represents the natural oral solubilization vehicle (compare with bile

composition)

• SPC added to overcome the hemolytic effect of the bile salt

• Mixed micelles are not hemolytic and have a low toxicity

State of the Art PL Component – Mixed Micelles

Purified Soybean PC (SPC)

with > 94% PC

LIPOID S 100
 Basic Components – Mixed Micelles

• Lipophilic API (vitamin K or other vitamins, diazepam, etc.)

• Soybean phosphatidylcholine (SPC)

• Glycocholic or deoxycholic acid

• Sodium hydroxide (for pH adjustment)

• Hydrochloric acid (for pH adjustment)

• Isotonizing agent (when required, e.g. in LVP)

• Water for injection

 Safety – Mixed Micelles

• Extensive pre-clinical safety testing of mixed micelles (placebo) has shown

the safety of injectable diazepam mixed micelles1

• Also pre-clinical safety of injectable mixed micelles containing partially

hydrolyzed lecithin (simulating long term storage of mixed micelles)
was studied1

• Safety assessment in humans shows safe use of mixed micelles in

i.v. injection2

1) Teelmann K, Schlaeppi B, Schuepbach MN, Kistler A 1984. Preclinical safety evaluation of

intravenously administered mixed micelles. Arzneim Forsch/ Drug Res 34(11):1517-1523

2) Ballinger AB, Forget D, LeBrun A, Farhting MJG 1996. An evaluation of the safety of mixed micelles
in healthy subjects. J Parenteral Enteral Nutrition 20(2):110-112
 Preparation – Mixed Micelles

General Considerations

• Ratio of excipients and maximal drug concentration is drug specific

• Ratio of phospholipids (SPC) and bile salt must be non-hemolytic

(normally in the range of 0.9 : 1 to 1 : 2)

• Soybean phosphatidylcholine and sodium glycocholate or sodium

deoxycholate are preferred (use in commercial products)

• Conversion to solid products is possible:

lyophilisates (parenteral), powders/tablets (oral)
Screening for Feasible Drug / Bile Salt / PL Ratio

All steps should be performed under nitrogen and preferably with exclusion of
light to avoid oxidation of the phospholipids:

• Assessment of feasible ratios of drug, phospholipid and bile salt in a suitable

solvent or solvent mixture to yield clear mixed micellar formulations

• Removal of the solvents by means of e.g. rota-evaporation followed by drying

under vacuum for 18 h (complexation)

• Hydration of the dry mixture at a suitable volume to adjust to the desired drug
concentration: Water for injection (for SVP) or sterile 5 % glucose (for LVP)

• Resulting mixed micelles are checked for presence of drug crystals/particles

(e.g. clarity, centrifugation, filtration)

• Determined ratio of formulation components which does not show undissolved

drug is used to prepare the mixed micelles without solvents
Preparation of Drug Containing Mixed Micelles

General Principles

• The crystal lattice energy of a crystalline drug, should first be overcome to

dissolve the drug in mixed micelles
• Low concentration mixed micelles are too mild (note: they are not
hemolytic) to dissolve a crystalline drug (thus, screening method uses
organic solvents!)

Manufacturing Methods Without Organic Solvents

I) Use of highly concentrated bile salt solution

II) Use of highly concentrated mixed micellar solution
Preparation of Drug Containing Mixed Micelles

Method 1: Use of a Highly Concentrated Bile Salt Solution

Sodium Glycocholate (2.86 g)

N2 atmosphere Water (6 ml), 20-25°C

30-40°C
Bile Salt Micelles (clear)

Vitamin K1 (0.5 g) Stirring

Bile Salt Micelles + Vitamin K1

LIPOID S 100 – SPC (3.78 g)

Stirring (16-20 h), 20-25°C
4 Portions, till completely dispersed

Conc. Mixed Micelles + Vitamin K1 (clear)

Water up to 50 ml
N2 atmosphere [Adjustment at pH 6]
Filtration (0.2 µm)

Final Mixed Micelles (50 ml)

Preparation of Drug Containing Mixed Micelles

Method 2: Use of Highly Concentrated Mixed Micellar Solution

Sodium Glycocholate (2.86 g)

N2 atmosphere Water (6 ml), 20-25°C

30-40°C
Bile Salt Micelles (clear)
LIPOID S 100 – SPC (3.78 g)
Stirring
4 Portions, till completely dispersed

Concentrated Mixed Micelles (clear)

Vitamin K1 (0.5 g) Stirring (16-20 h), 20-25°C

Conc. Mixed Micelles + Vitamin K1 (clear)

Water up to 50 ml
N2 atmosphere [Adjustment at pH 6]
Filtration (0.2 µm)

Final Mixed Micelles (50 ml)

 Commercial Examples – Mixed Micelles

Brand Name API Type of PL Indication Year Producer

Lipostabil® N i.v. Purified soybean PC Purified soybean PC** Atherosclerosis 1950 Sanofi
(Nattermann)
Essentiale® N i.v. “Essential Phospholipids” Purified soybean PC** Liver therapy 1950 Sanofi
(Nattermann)
Valium MM® Diazepam Purified soybean PC** Sedative 1986 Roche

Cernevit® Vitamin blend (fat and water Purified soybean PC** Parenteral nutrition, 1999 Baxter
soluble vitamins) Vitamin supplement
Rimadyl® Injection Carprofen Purified soybean PC** Pain relief, 2000 Pfizer
(Veterinary drug) anti-inflammation
Konakion® MM Vitamin K1 Purified soybean PC** Vitamin K deficiency 2003 Roche
oral / i.m. / i.v.

** like LIPOID S 100

 Further Experimental Use – Mixed Micelles

Examples for APIs

• Teniposide • Indomethacin
• Taxol • 20(R)-Ginsenoside Rg3 (G-Rg3)
• Amphotericin B • Ivermectin
• Cyclosporine • Curcumin
• Tetrazepam
• Lorazepam
• Clonazepam

(Literature available on request)

 Summary and Conclusions

• Excipients used in MM are non-toxic, biocompatible, and natural components

• Natural Soybean Phosphatidylcholine (n.l.t. 94%) is used
• Have no risk for anaphylactic reactions compared to synthetic solubilizers like
Tween, Cremophor, and Solutol
• Are used worldwide in marketed products suggesting adequate stability and
acceptance by regulatory authorities

• Mixed micelles are safe and non-hemolytic

• Are suitable for pediatric use (oral)
• Are suitable for oral and parenteral development allowing a very efficient
pharmaceutical development of dosage forms
• Can be produced at large scale using simple technologies compared to
liposomes and emulsions
• Can be freeze dried when needed

Mixed micelles present a very attractive

solubilizing formulation technology!