The Properties and Functions of Vitamin E TPGS - IPEC

11.05.2015
The Properties and Functions
of Vitamin E TPGS
Vitamin E polyethylene glycol succinate
Nigel Langley
ExcipientFest 2015
Introduction
Permeability
The need for solubilizers
Class II
Class I
70%
5%
90%
Class IV
Class III
20%
5%
Solubility
0.1 mg/mL
About 95% of all new chemical entities (NCE) show
poor solubility and/or poor permeability
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Introduction
Enhancement of “Biopharmaceutical Fitness”
Permeability
Enhancement of solubility
•
•
•
•
•
•
pH-adjustment
co-solvents
surfactant systems (incl. SEDDS)
complexation
micronization / nano
…
Class I
5%
90%
Enhancement of permeability
•
•
•
•
•
Enhancement of permeability
&
Enhancement of solubility
Solubility
tight junction openers
metabolic inhibitors
motility modifier
pro-drugs
efflux inhibitors (P-gp)
0.1 mg/mL
Excipients with various functions are useful to increase
biopharmaceutical fitness of Class II-IV substances
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Vitamin E TPGS
Kolliphor™ TPGS
Chemical composition
polyethylene
glycol 1,000
succinate
vitamin E (D-alpha tocopherol)
O
HO
O
O
n
O
O
n=~22
 Kolliphor™ TPGS is produced by esterification of natural vitamin E succinate with
polyethylene glycol (1,000 Da)
 It contains high amounts of mono-ester (main component ~87%), but also
di-esters (~7%) and free PEG (~2-3%)
 Mw~1,500 Da (main component); potency of vitamin E ~420 I.U./g
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Kolliphor™ TPGS properties
Overview of properties
Names
Vitamin E polyethylene glycol succinate (USP)
Tocophersolan (INCI / INN)
TPGS, Tocofersolan, vitamin E TPGS (Synonyms)
Appearance
White to light brown waxy solid
Gardner color
Max. 10 (usually ~3)
Vitamin E content
260 – 300 mg/g (as D-α-tocopherol)
Melting point
37 – 40 °C
Specific gravity
Approx. 1.06 (45 °C)
HLB value
Approx. 13
Critical micelle concentration (CMC)
0.02 %(m/m) at 37 °C (surface tension method)
Solubility in water
Miscible in all parts
Dynamic viscosity
1.5 mPa*s (22 °C; 5% solution in water)
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Kolliphor® TPGS resists stress
20x
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Crystallization
24h @ RT
Melting
24h @
65°C
20x
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Kolliphor® TPGS resists stress
Keep for
5 days
at 80°C
Melting
Cool down
and analyse
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Thermal properties – Melting Point
30.0
400
TPGS was not pre-conditioned prior DSC measurement
350
25.0
cp (J/g*K)
250
15.0
200
150
10.0
Enthalpie (J/g)
300
20.0
100
5.0
50
0.0
0
-40
-20
0
20
40
60
Temperature (°C)
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Specific Heat Capacity and thermal stability
of Kolliphor® TPGS
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• Thermally stable until 200°C
• Flash point (DIN EN ISO 2592):
286°C
• Inflammation point: 384°C
cp [J/gK]
20
15
10
5
0
15
35
55
Temperature [°C]
MSDS:
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By the way – how does TPGS crystallize?
Cooling
from
outside to
inside
Decreasing
Volume
TPGS.mp4
Nuclei
growth
Nuclei
formation
on surface
Timelapse video wraps 5h into 20s
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Kolliphor™ TPGS applications
Fields of Application
Enhancement of
Bioavailability
Excipient in
melt extrusion
 Increase solubility of
poorly water-soluble
APIs
 Versatile plasticizer
with solubilization
properties
 Formulation of
SEDDS
 Antioxidant for
sensitive excipients
Source of natural
vitamin E
 For patients suffering
from vitamin E
malabsorption
(cholestatic disease)*
 Water-soluble
vitamin E in dietary
supplements
*GMP production according to ICH Q7 needed
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High Throughput Screening (HTS)
Analytics
UV/VIS, PSD
Automation
High-Throughput-robot
Combination
Effective and fast screening of solubilization capacity of different solubilizers
for various APIs
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Status Set up of HTS
UV testing method is integrated
Testing

UV/VIS detection

automatic dilution

modular set up allows
integration of a variety
of analytical tools
Kolliphor™ TPGS applications – Enhancement of bioavailability
Increase of solubility
Source: BASF / Determination of thermodynamic solubility with a high-throughput robot
3000
buffer
1%
5%
10%
Solubility /ppm
2500
2000
1500
1000
500
118
0
Carbamazepine
<5
Danazol
<5
Piroxicam
<5
Fenofibrate
<5
Cinnarizine
 Massive increase of solubility was observed for all tested APIs (Solu-HTS)
 No dependency on chemical structure
 Almost linear increase of solubility and concentration for most APIs
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Kolliphor™ TPGS applications – Enhancement of bioavailability
Furosemide solid dispersion
S.-C. Shin, J. Kim; Int. J. Pharm., 251 (2003), 79-84
 Solid dispersions of furosemide and
TPGS were prepared by solvent
method using methanol
 Amorphous state of solid dispersion
was proven by XRD and thermal
analysis
 Dissolution rate and speed was
markedly enhanced for solid
dispersion compared to pure API and
to physical mixture
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Kolliphor™ TPGS applications – Enhancement of bioavailability
Oral bioavailability Paclitaxel
M.V.S. Varma, R. Panchagnula ; Eur. J. Pharm. Sci., 25 (2005), 445-453
 Paclitaxel solubility is significantly increased by TPGS (left)
 Oral bioavailability of Paclitaxel is enhanced in combination with
TPGS (right)
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Kolliphor™ TPGS applications – Enhancement of bioavailability
Increased absorption flux of Amprenavir
L. Yu et al., Pharm. Res., 16 (1999), 1812-1817
 Above its CMC TPGS increases solubility of Amprenavir linearly (left)
 TPGS also inhibits the efflux system
 As a result of both, the absorption flux of Amprenavir is increased (right)
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Kolliphor™ TPGS applications – Excipient in melt extrusion
Improvement of processability
M.A. Repka, J.W. McGinity; Int. J. Pharm., 202 (2000), 63-70
 TPGS acts as plasticizer for HPC/PEO combinations and reduces the
glass transition temperature (left)
 Lower degradation during extrusion is achieved (GPC, right)
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Kolliphor™ TPGS applications – Excipient in melt extrusion
Properties of film extrudates
M.A. Repka, J.W. McGinity; Int. J. Pharm., 202 (2000), 63-70
 Elongation at break of extruded HPC/PEO films increases with
increasing amounts of TPGS (left)
 Increase of elongation is much higher than with conventional plasticizers
(TEC, ATBC), however little lower compared to PEG 400 (right)
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Kolliphor™ TPGS applications – Source of natural vitamin E
Vitamin E for malabsorbing patients
K. Papas, Dig. Dis. Sci., 52 (2007), 347-352
 A TPGS formulation (Aqua-E) was
compared to an oily formulation(Soft
gel) of vitamin E
 Children, suffering from cystic fibrosis,
showed massively enhanced plasma
levels of tocopherol after intake of
TPGS formulation
 AUC values were about three times
higher for TPGS formulation compared
to oily formulation
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Kolliphor™ TPGS market
Registered products – IID listing
 Inactive ingredient database lists several approved drug products
 Besides oral solutions and capsule formulations also ophthalmic and topical
solutions are found
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Products using Tocophersolan
Vedrop
50 mg/ml oral solution
 Each ml contains 50 mg
of d-alpha-tocopherol, in
the form of tocofersolan,
corresponding to 74.5 IU
of tocopherol
APTIVUS
oral solution
 Tipranavir, protease
inhibitor of HIV-1
 Each milliliter of APTIVUS
oral solution contains 116
IU of vitamin E, and when
taken at the recommended
maximum dose of 500
mg/200 mg
tipranavir/ritonavir BID
results in a daily dose of
1160 IU.
AGENERASE
soft gel capsules
 Amprenavir,
 The total amount of vitamin
E in the recommended
daily adult dose of
AGENERASE is 1,744 IU.
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Products using Tocophersolan
Agenerase
Oral Solution
Viekira Pak
tablets
 Solution contains 46 IU
 Treats Hepatitis C
vitamin E in the form of
 Ombitasvir, Paritaprevir,
TPGS. Propylene glycol is
Ritonavir Fixed-Dose
in the formulation to
Combination
achieve adequate solubility
 tablet contains
of amprenavir.
copovidone, vitamin E
polyethylene glycol
succinate…
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Kolliphor™ TPGS toxicological information
Upper intake levels (UL) for vitamin E
Institute of Medicine. Food and Nutrition Board. Washington, DC: National Academy Press, 2000.
Age
Male
Female
1-3 years
200 mg
(300 I.U.)
200 mg
(300 I.U.)
4-8 years
300 mg
(450 I.U.)
300 mg
(450 I.U.)
9-13 years
600 mg
(900 I.U.)
600 mg
(900 I.U.)
14-18 years
800 mg
800 mg
(1,200 I.U.) (1,200 I.U.)
19+ years
1,000 mg
1,000 mg
(1,500 I.U.) (1,500 I.U.)
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 The maximum daily intake of TPGS is
probably set by the vitamin E content
 Recommended dietary allowance for
vitamin E is quite low: 15 mg (~23 I.U.)
for adults
 However, the upper intake levels are
much higher: 1,000 mg for adults
irrespective of gender
 This corresponds to a maximum daily
intake of ~3.5 g for TPGS
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Vitamin E TPGS
Kolliphor™ TPGS
Enhances bioavailability of poorly soluble APIs
Improves processability in melt extrusion
Serves as effective, non-acidic antioxidant
Delivers water-soluble, natural vitamin E
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