excipients fpr lipid formulations_aapsworkshop
TRANSCRIPT
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Colin W. Pouton
Victorian College of Pharmacy, Monash University, Melbourne, Australia
E-mail: [email protected]
Phone: + 61 3 9903 9562
Properties and Uses of Common Formulation
Lipids, Surfactants and Cosolvents
AAPS Workshop March 2007
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Excipients for lipid formulations
Hydro
phobic
Hydro
philic
liquids waxes
mineral oils petrolatumvegetable oils hydrogenated vegetable oilsMCT oil, diglycerides monoglycerides
glyceryl mono-oleate glyceryl mono-stearatesorbitan oleates (Spans 80, 85) sorbitan stearateesters
POE-oleate estersPOE triglceridespolysorbate 85 POE hydrogenated veg oils
polysorbate 80, Cremophor EL polysorbate 20
PEG 400, propylene glycol PEG > 1500
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General Issues in excipient selection
• Regulatory issues – irritancy, toxicity, knowledge and experience
• Solvent capacity
• Miscibility
• Morphology at room temperature (i.e. melting point)
• Self-dispersibility and role in promoting self-dispersion of the formulation
• Digestibility, and fate of digested products
• Capsule compatibility
• Purity, chemical stability
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Regulatory Issues in excipient selection
• Amongst typical excipients for lipid materials surfactants cause the most concern
• Hydrophobic surfactants can penetrate membranes causing changes in membrane fluidity and permeability. Generally singlealkyl chains are more penetrative, so bulky surfactants such as polysorbates and triglyceride ethoxylates are less ‘toxic’
• Hydrophilic surfactants can extract lipids into the aqueous phase and destroy membranes.
• In animal toxicity studies – cationics > anionics > nonionics
• Toxicity of nonionics – single chain ethers > single chain esters > bulky esters (most commonly used are bulky esters)
• Acute LD50 values for nonionics in rodents are 5-10 g/kg (IV), >50g/kg (oral). Some chronic studies are available for a wide variety of surfactants (see textbooks of Schick, and Attwood and Florence)
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Regulatory Issues in excipient selection – in practice
• Animal data suggests that most nonionic surfactants are equal – but in practice some are more equal than others!
• The choice of surfactants is often driven by prior use in existing food and pharmaceutical products, for fear of failure late in toxicity tests
• Food substances classed as GRAS (generally recognized as safe) will be favoured
• The US FDA Center for Drug Evaluation and Research has now posted a database of excipients – the ‘Inactive Ingredients Database’ which states the masses or concentrations of ingredients used in marketed pharmaceutical products (see www.fda.gov/cder)
• To use a new excipient may imply a cost of about $20 million for full toxicity evaluation - a new draft guidance document is posted at cder website (see www.fda.gov/cder/guidance/3812dft.doc)
• The inactive ingredients database will be a major driver in the future
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Capsule compatibility
• Lipid systems can be filled into soft or hard gelatin providing an effective sealing system is available for hard gelatin
• Maintaining water in formulations is difficult – note that water moves into and out of softgel capsules. w/o emulsions and microemulsionscan lose water quickly during drying of softgels.
• Other low molecular weight polar compounds (eg propylene glycol)can cause compatibility problems at high concentration
• Virtue of working with capsule filling companies is to access the wealth of knowledge on gelatin formulation and excipient compatibility
• Soft and hard gel manufacturers are working hard to improve compatibility and move to non-animal sources for capsule shell materials
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Miscibility of excipients
• Oils and cosolvents are generally not miscible, but the inclusion of polar oils (such as mono and diglycerides) or surfactants createsingle phase solutions.
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Solubility in lipid formulations
Take care to ensure solubility measurements in oily formulations are reliableAlways have crystalline solid present in excess – leave enough time for equilibration
In the experiment below testosterone was mixed with a lipid formulation at thetemperature shown then allowed to equilibrate at 25oC over a week
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Waxy versus liquid excipients
• Esters with saturated alkyl chains >C12 tend to crystallize at ambient temperatures
• Monoglycerides crystallize at higher temps than di- or triglycerides
• Hydrophilic surfactants with high PEG content tend to be waxy, unless unsaturatedglycerides are predominant
• Liquid formulations are desirable to avoid morphological changes due to crystallization during storage – but beware of slow crystallization if close to a phase boundary
• ‘Solid solutions’ could allow presentation of the drug in an amorphous form but are at risk of re-crystallization
Typical liquid excipients
• medium chain di and triglycerides (monoglycerides are crystalline but blends with diand triglycerides are liquid)
• unsaturated long-chain triglycerides (typical vegetable oils) and hydrolysed oils as long as the monoglyceride content is low (NB - consider Maisine)
• unsaturated or medium chain ethoxylates (eg. polysorbate 80, Labrasol)
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Lipids
• ‘Pure’ lipids relatively easy to classify
• Typically glycerides derived from plants
• Most simply triglycerides, but also more polar mono and di-glycerides
• Fatty acids also occasionally used, although possible problems with stability (esterification) and irritancy (especially with shorter chain lipids)
• Key issues for glycerides are residual fatty acids
• Several providers of refined or super-refined lipids, usually more specific wrt fatty acid chain lengths/unsaturation, and or residual fatty acid
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Fatty acid composition of common oils
0.228.364.21.0Apricot kernel
45.041.04.09.0Sesame
2.015.03.08.016.048.04.0Palm kernel
036.048.04.012.0Peanut
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C18:1 - OH
3.07.01.02.0Castor
0.267.920.73.56.2Sunflower
7.851.521.53.510.4Soybean
0.481.411.11.65.5Safflower
10.040.04.045.01.0Palm
0.910.771.22.012.9Olive
1.161.324.51.610.7Corn
03.117.82.89.616.644.42.72.4Coconut
9.121.760.02.04.7Canola
C18:3C18:2C18:1C18C16C14C12C10C8Oil
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Polar Lipids
• e.g. lipids such as monoglycerides, propylene glycol esters and diesters, and sorbitan esters
• these materials typically are poorly soluble in water but have free hydroxyl groups which can hydrogen bond with water, surfactants, cosolvents etc.
• polar lipids typically are better solvents for drugs
• polar lipids act as ‘co-surfactants’ which promote mutual solubility between excipients, enhance water uptake, and promote self-dispersibility of lipid formulations
• Polar lipids are vital components of Type II and Type III lipid formulations
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Medium Chain Triglycerides
• Triglycerides of fractionated vegetable C8 and C10 fatty acids (usually fractionated coconut oil). Several manufacturers produce MCTs which meet USP/EP spec.
• Saturated, stable, liquids, good solvent properties
• Miglyol 810/812
– 810 C8 (65-80%); C10 (20-35%)
– 812 C8 (50-65%); C10 (30-45%)
• Captex 300, 355, Neobee M5, Crodamol GTC/C
• Labrafac Lipophile WL 1349 (EP/USP Spec)
– C8 (50-80%); C10 (20-50%); C12 (<3%)
• Also variations on a theme with slightly differing FA proportions
– Miglyol 818 C8 (45-65%); C10 (30-45%); C18:2 (2-5%)
– Captex 810D C8-10 (max 40%); C18:2 (max 40%)
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Medium Chain Mono and Diglycerides
Usually mono and diglycerides of capric (C10) and caprylic (C8) FA, with traces of TG
• Capmul (Abitec)
– Capmul MCM (58% MG, 36% DG, 5% TG; 80% C8, 20% C10)
– Capmul MCM C8 (68% MG, 27% DG, 3% TG; >95% C8, 3% C10; )
– Capmul MCM C10 (> 45% MG; >45% C10)
• Imwitor (Sasol)
– Imwitor 988 (MG/DG/TG of primarily caprylic (C8) acid; 47-57% MG)
– Imwitor 742 (MG/DG/TG of C8 and C10 FA; 45-55% MG)
– Imwitor 928 (MG/DG/TG of saturated FA of coconut oil (mainly C12)
min 40% MG)
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Long Chain Mono and Diglyceride blends
• Typically a mixture of MG, DG and smaller quantities of TG
• Typical products:
– Peceol: Glyceryl monooleate HLB 3.3 Glyceride content: MG: 32-52%; DG 30-50%; TG: 5-20%
FA Composition: C18:1>60%; C18:2<35%; C18:0<6%; C16<12%0-5%
– Maisine 35-1: Glyceryl monolinoleate HLB = 4
Glyceride content: MG: 32-52%, DG: 40-55%, TG 5-20%
FA Composition: C18:2 >50% max; C18:1 10-35%; C18:0 <6%; C16 4-20%
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Propylene glycol esters
O
Name R (fatty acid)
> 90% Monoester of C8 (caprylic
acid)
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Capryol 90
Propylene glycol monocaprylate 90%
HLB
> 60% Monoester
> 90% C8
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Capryol PGMC
Propylene glycol caprylate
C10/C12 2
Labrafac PG
Propylene glycol dicaprylocaprate
Note
V low HLB, actually functions as lipophilic solvent cfMCT
R-C-O-CH2CHOH-CH3
Possible effects on P-gp (poster
#T3124, AAPS 05)
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Propylene glycol esters: Lauroglycol
R-C-O-CH2CHOH-CH3
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Name R (fatty acid) HLB
> 90% Monoester > 95% C12 (lauricacid)
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Lauroglycol 90
Propylene glycol monolaurate
45-70% Monoester30-55% Diester> 95% C12
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Lauroglycol FCC
Propylene glycol laurate
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Notes on surfactants, cosurfactants for lipid formulations
• Cremophors (castor oil ethoxylates), Gelucires, Labrosol are remarkably good for SMEDDS formulations with no apparent advantage of unsaturation (ie. Cremophor EL versus RH40).
• Polar oils (eg. MGs, DGs, oleic acid) are critical components of many formulations. They promote water penetration and have good solvent capacity for drugs. Choice of medium chain or long chain materials is influenced by several considerations:
- medium chain glycerides are better solvents, not prone to oxidation
- digestion products of long chain glycerides may be beneficial
- MGs are more crystalline: glyceryl monooleate is semi-solid
• Surfactants with high ethoxylate content are waxy
• Digestibility of surfactants may have a critical influence – more work is needed in this area (ethers versus esters, effect of concentration)
• Some unusual surfactants have become popular (TPGS)
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Notes on surfactants
• Ethoxylated surfactants can be synthesised by direct reaction with ethylene oxide, or by esterification reactions with PEG.
• Many commonly used triglyceride ethoxylates are formed by hydrolysis of triglycerides and then esterification with PEG. This results in a wide range of molecules: free oils, ethoxylated TGs, ethoxylated DGs, ethoxylated MGs, ethoxylated glycerol, free PEG, all of which are polymeric
• As a result Labrosol, Labrafils, Gelucires, Cremophor RH40 and EL contain hundreds of individual molecules. Polysorbates are much less heterogeneous.
• Labrasol (medium chain ethoxylate) acts like a formulated SEDDS when introduced to water (ie. oil, cosurfactant, surfactant, cosolvent –all in one excipient).
• Poloxamers are good quality materials but their molecular weight makes them less mobile and reduces their performance as self-emulsifying systems
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Surfactants: Polyethoxylated lipids
• Many of the surfactant systems used in contemporary lipid based formulations are variations on a theme of polyethoxylated lipids
• The lipids may be fatty acids, alcohols or glycerides and are linked to any number of repeating polyethylene oxide units typically by ester links (glycerides, fatty acids), and occasionally by ether linkages (alcohols)
• Although the hydrophilic group is often PEG, this is not always the case, and can be other glycols etc
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General Schematic: Surfactant production
• Products obtained by esterification of vegetable fats or oils or fatty acids with glycols, polyethylene glycols or alcohols, or alternatively by reaction of fatty acids, fatty alcohols with oxyethylene
• Raw materials from vegetable origin
• Combination of a hydroxyl group substrate with an alkyl tail
Fatty acids or glycerideswith various lengths: Caprylate, caprylic, lauric, stearic, ..
Lipophilic Chain
PEGPropylene glycolGlycerol
Hydrophilic head group
Provides the amphiphilicity of surfactants
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Polyethoxylated fatty acid esters, e.g. Myrj
Myrj 45
PEG 400 monostearate
Polyoxy 8 stearate
R-C-(O-CH2-CH2)n-OH
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Name R (fatty acid) PEG mol wt n HLB
Stearic (C18) acid 400 8 11.1
Solutol HS 15
PEG 660 hydroxy-stearate
Macrogol 15 hydroxy-stearate
12-hydroxystearic (C18) acid
660 15 14-16
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Polyethoxylated alkyl ethers, e.g. Brij
R-(O-CH2-CH2)n-OH
Name R (alcohol) PEG mol wt n HLB
Oleyl (C18:1) ~450 10 12.4Brij 97
Polyoxyl 10 oleyl ether
Oleth 10
PEG monooleyl ether
Stearic (C18) and Cetyl (C16)
~1100 25 15-17Cremophor A 25
Macrogol 25 cetostearyl ether
(Cetomacrogol)
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Polyethoxylated sorbitan esters (polysorbates) e.g. Tweens
Name R (fatty acid) POEn HLB
Oleyl (C18:1)
trioleyl (C18:1)
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20
15.0
11.5
Tween 80
Tween 85
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Polyethoxylated glycerides: e.g. Cremophor
Name R (fatty acid) PEG mol wt n
Castor oil - TG of ricinoleic acid (12-
hydroxyoleic acid)
1600 35 12-14
Cremophor EL
Polyoxyl 35 Castor oil
Glycerol polyethylene glycol ricinoleate
R is ricinoleic acid based glycerides (ie from castor oil). The PEG chain is linked to side OH groups of the ricinoleate chains.
Hydrogenated Castor oil - TG of oxystearic acid
1600 40 14-16
Cremophor RH 40
Polyoxyl 40 hydro-genated castor oil
Glycerol polyethylene glycol oxystearate
HLB
Also contains mono, di and triglycerides, and some free PEG
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Polyethoxylated glycerides: e.g. Labrafils
Name R (fatty acid) PEG mol wt n
Mixed glycerides of
C18:1 - 58-80%
C18:2 – 15-35%
C16 – 4-9%
C18 - <6%
300 6 4
Labrafil M 1944
PEG 300 oleic glycerides
Oleoyl Macrogol-6 glycerides
HLB
Formed by esterification of PEG 300 and apricot kernel oil.
Labrafil is composed of tri and partial glycerides and esters of PEG 300
Both also contain mono, di and triglycerides, and some free PEG
As above but greater C18:2composition
300 6 4
Labrafil M 2125
PEG 300 linoleicglycerides
Linoleoyl Macrogol-6-glycerides
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Polyethoxylated glycerides: e.g. Labrasol
Name R (fatty acid) PEG mol wt n
Mixed glycerides of
C8 - 50-80%
C10 – 20-50%
C12 – < 3%
C18 - <6%
400 8 14
Labrasol
PEG 8 caprylic/capric glycerides
Caprylcaproylpolyoxyglycerides
HLB
Also contains some free PEG
Formed by esterification of PEG 400 and medium chain triglyceride oil.
Labrasol is composed of tri and partial glycerides and esters of PEG 400
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Waxy Polyethoxylated glycerides: e.g. Gelucire 44/14
Name R (fatty acid) PEG mol wt n
Mixed glycerides of
C12 – 40-50%
C14 – 14-24%
C8 – 4-10%
C10 – 3-9%
C16 – 4-14%
C18 – 5-15%
1500 32 14
Gelucire 44/14
hydrogenated palm kernel oil PEG-32 esters
lauryl polyoxyglycerides
lauryl macrogolglycerides
HLB
Formed by esterification of PEG 1500 and hydrogenated palm kernel oil
Gelucire 44/14 is composed of partial glycerides and esters of PEG 1500
Nomenclature: HLB/Mpt eg 44/14
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Polyethoxylated glycerides: e.g. Gelucire 50/13
Name R (fatty acid) PEG mol wt n
Mixed glycerides of
C16 – 40-50%
C18 – 48-58%
C16+18 - >90%
1500 32 13
Gelucire 50/13
stearoylpolyoxyglycerides
stearylmacrogolglycerides
HLB
Formed by esterification of PEG 1500 and hydrogenated palm oil
Gelucire 50/13 is composed of partial glycerides and esters of PEG 1500
Nomenclature: Mpt/HLB eg 50/13
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Poly-glycerol esters: e.g. Plurol Oleique
Plurol Oleique CC497; (polyglyceryl-3-dioleate)
Diesters of oleic acid with a glycerin polymer (containing n=3 repeating glycerin units)
HLB = 6
Plurol Oleique (polyglyceryl-6-dioleate)
Diesters of oleic acid with a glycerin polymer (containing n=6 repeating glycerin units)
HLB = 10
1o Oral applications, Pharma grade
1o cosmetic or topical pharma applications
OH-(CH2-CH-CH2-O-)nH
OH Primarily di- and tri-oleic acid esters of polyglcerolR-C-O-
O
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TPGS and poloxamers
TPGS: D-a-tocopheryl PEG 1000 succinate (MW = 1513)
Formed as esterification product between acid group of Vit E and PEG 1000
Used as an emulsifier (HLB ~13)
Also possible effects on eg P-gp efflux
General structure of poloxamers
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Cosolvents
C2H5-O-CH2-CH2-O-CH2-CH2-OH
Diethylene glycol monoethyl ether (Transcutol)
Propylene glycol
Polyethylene glycol (PEG), polyoxyethylene
Ethanol
Propylene carbonate
Glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether)
Acknowledgements
University of Bath, UKMark WakerlyDebbie ChallisLinda SolomonNaser HasanRajaa Al Sukhun
Victorian College of PharmacyDallas WarrenKazi MohsinJean Cuine Chris Porter Bill Charman
R P Scherer Ltd. digestion experiments 1991-1994
Cardinal Healthmolecular dynamics modeling 2002-2004
Abbott Laboratoriesrecent formulation work 2002-2006
Capsugelin vitro-in vivo correlation 2003-2006Support for LFCS