We've come a long, long way together: investigating

We’ve come a long, long way together: investigating the fascinating structures and functions of lipid excipients in drug delivery Dr Vincent Jannin (Gattefossé) and Pr. Ben J. Boyd (Monash University) Gattefossé Foundation, Saint-Rémy-de-Provence, September 2018

Lipids excipients in drug delivery For most scientists, this is it!

Lipids excipients in drug delivery Today’s topic

Lipids • Lipid-based excipients are ingredients derived from vegetable oils, fatty acids or waxes. • Vegetable oils comprise triacylglycerols – fatty acid esters of glycerol – phospholipids and lipophilic vitamins. • Waxes comprise mainly fatty acid esters of long chain alcohol. • Common building blocks of lipids are fatty acids.

Jannin, V., et al. 2008. Approaches for the development of solid and semi solid lipid-based formulations. Adv. Drug Deliv. Rev., 60 (6) 734-746.

Fatty acids, at least 8 carbons, even numbered Medium chain fatty acids

• C8:0 • C10:0 • C12:0

Caprylic acidMP=17°C Capric acid MP=32°C Lauric acid MP=45°C

Long chain fatty acids

• C14:0 • C16:0 • C18:0

Myristic acid Palmitic acid Stearic acid

MP=54°C MP=63°C MP=70°C

Unsaturated fatty acids Always in cis conformation C18:1 Oleic acid

MP=16°C

C18:1(OH)

Ricinoleic acid MP=6C

Alcohols used to manufacture lipid-based excipients by esterification or alcoholysis HO

Glycerol

OH

OH

Propylene glycol OH

OH

H HO

O

n OH

Polyglycerol

O HO

H n

Polyethylene-glycol (PEG)

Structure/physchem properties relationship 1. Ability to organize in lamella O

O

OH

1,3-propanediol laurate Solid at RT O

O

1,2-propanediol laurate Liquid at RT

OH

Structure/physchem properties relationship 2. Impact of chain length Liquid O

Caprylyl ether C8C8

Solid

O O

Stearyl stearate C18C18

Structure/physchem properties relationship 3. Impact of unsaturation (esters of fatty acids and alcohol C20-22-24) Jojoba wax Liquid at RT

O O

Sunflower wax Solid at RT (MP=80°C) O O

Structure/physchem properties relationship 4. Impact of branched molecules Stearyl stearate Solid

Isostearyl isostearate Liquid

O O

O O

Structure/physchem properties relationship 5. Impact of intermolecular bonding

H O O

O

OH O

H 2C CH

O

H 2C O

O

Castor oil (viscous)

O H H O O

O

OH O

H 2C CH

O

H2 C O

O O H

All solid lipids are polymorphic Glyceryl behenate

Lauroyl polyoxylglycerides

Brubach, J.B., et al. 2007. Structural and thermal characterization of glycerol mono-, di- and tribehenate by X-ray diffraction coupled to differential calorimetry and infrared spectroscopy. Int. J. Pharm., 336, 248-256. / Jannin, V. 2009 Lauroyl polyoxylglycerides, functionalized coconut oil, enhancing the bioavailability of poorly soluble active substances. OCL, 16, 267-272

Polar lipids Class I Insoluble amphiphiles, non swelling Stable monomolecular films

Class II Insoluble amphiphiles, swelling Stable monomolecular films

Class III Partially soluble amphiphiles Unstable monomolecular films

Crystals or emulsions in water Eg. Triacylglycerols, cholesterol

Liquid crystals in water Phospholipids, monoacylglycerols

Monomeres or micelles in water Biliairy salts, surfactants

Small, D. M., 1968. A classification of biologic lipids based upon their interaction in aqueous systems. J. Am. Oil Chem. Soc. 45, 108.

Critical Material Attributes

Jannin, V., et al. 2014. Polyoxylglycerides and glycerides: effect of manufacture on API stability, excipient functionality and processing. Int. J. Pharm., 466. 109-121.

‘Lipid self-assembly is key to function’ • Lipids should not be thought of as an inert lipophilic material • Polar lipids self-assemble in aqueous environments Increasing water/hydrophilicity Increasing lipid/hydrophobicity

For oral lipid formulations digestion is usually a key process triglyceride

glycerol

triglyceride diglyceride + fatty acid monoglyceride + fatty acid

lipase

monoglyceride glycerol

Fatty acids

How we study digestion driven self assembly Small angle X-ray scattering (SAXS) Synchrotron X- ray source

Sample

Detector

integrate

Drugs +milk etc

Digestion of milk follows the ‘rules’ for self-assembly for increasingly polar lipids

Salentinig, S., et al. (2013). "Formation of Highly Organized Nanostructures during the Digestion of Milk." ACS Nano 7(12): 10904-10911. Salentinig, S., et al. (2015). "Self-Assembly Structure Formation during the Digestion of Human Breast Milk." Angewandte Chemie International Edition 54(5): 1600-1603.

Lipids and lipophilic drugs Many BCS Class II drugs fail in development due to limited aqueous solubility But, are soluble in lipids by definition

Nature – why fight it in application? triglyceride

glycerol

monoglyceride glycerol

Fatty acids

Formulation paradigm: Maximise dissolved drug and keep it in solution despite digestion. If drug precipitates it will be bad.

Nature’s paradigm: Get drug into dissolved state immediate prior to absorption. The rest will take care of itself.

Work with Nature to harness these processes?

Example 1 – formulation, digestion and solubilisation in milk Intensity of Cinnarizine diffraction peak 50

Suspension in undigested milk

Drug present in crystalline form before digestion Track loss of peak over time during digestion

Intensity

40

cinnarizine

30

20

Dissolved in digested milk

10

0 0

1000

2000

3000

4000

Time (secs)

Follow drug rather than lipid self assembly – “how much crystalline drug remains after digestion”?

5000

Example 2 – rational selection of infant formula as an excipient 500000 children die pa before their 5th birthday from malaria

OZ439

Ferroquine

High ‘apparent’ aqueous solubility*

Poor aqueous solubility

= Sufficient exposure

Can IF enable a medicine?

• Digestion is critical, lipid amount, and lipid type are critical • Phase 2b has confirmed these results in vivo

So it does matter what lipids are used Opportunity for rational design of even better lipid systems from commercial sources Select glycerides to give best outcome for given drug triglyceride glycerol

monoglyceride glycerol

Fatty acids

Summary so far…. • Lipids are versatile in structure, self-assembly, digestion products • Digestion can provide effective solubilisation for weakly basic poorly soluble drugs • The fatty acid composition can be critical • But – its not all about poorly-soluble weak bases! …

Lipid Formulation Classification System

Formulation

Composition

Characteristics

Type I

Oils

Type II

Oils Low-HLB surfactants

Type III