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Excipients as Absorption Enhancers ForDrug Delivery Applications
(A Case Study Using Vitamin E TPGS, NF)
Excipients as Absorption Enhancers ForDrug Delivery Applications
(A Case Study Using Vitamin E TPGS, NF)
Presented by
Stephen H. W. Wu, Ph.D
Pharmaceutical Formulation LaboratoryEastman Chemical Company
Need and Concerns for Using Absorption Enhancers in Drug Delivery Systems
Many new drug candidates exhibit poor water-solubility, poor permeability, and thus poor bioavailability.
Solubilizing the drug in a liquid, solid or semi-solid (soft gel capsule) formulation is needed.
Main concerns are effectiveness, mechanism and toxicity
Outline
1. An overview of drug solubilization and absorption enhancers
2. Structure and typical properties of vitamin E TPGS
3. Known applications
4. Milestones in the development of vitamin E TPGS
5. Thermal properties
6. Liquid crystalline and solution properties
7. Mechanism of absorption enhancement
8. An example: Amprenavir(Agenerase by Glaxo Wellcome in 1999)
9. References and patent art
Critical Issues of Using Absorption Enhancers
Critical Issues of Using Absorption Enhancers
Effectiveness of bioavailablity enhancement
- Effective concentration at the site of
absorption
- Site-dependent
- Inter-subject variability
- Formulation and physiologic variables
Mechanism of permeation enhancement
Toxicity
Effectiveness of bioavailablity enhancement
- Effective concentration at the site of
absorption
- Site-dependent
- Inter-subject variability
- Formulation and physiologic variables
Mechanism of permeation enhancement
Toxicity
Vitamin E TPGS NF Water-miscible form of vitamin E derivative
Structure-property relationship suggests that
it may uniquely meet the need for enhancing
drug solubility, permeability, safety and
hence bioavailabilty
(CH2)2(CH2)2
CCOO
OO
COO(CH2CH2O)nHCOO(CH2CH2O)nH
CH3CH3
CH3CH3
H3CH3C OO
CH3CH3CH3CH3 CH3CH3
CH3CH3
CH3CH3
Eastman Vitamin E TPGS NF(d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate)
Eastman Vitamin E TPGS NF(d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate)
Key Attributes of Vitamin E TPGSKey Attributes of Vitamin E TPGS
Average MW ~ 1513
Waxy solid m.p. 37 - 41 C
Water-miscibility miscible in all parts
Solubility in PEG 400 miscible
HLB Value ~13.2
Liquid crystal structures solution gel
Stability in aqueous media stable at pH 4.5 - 7.5 hydrolyzed in the body
Vitamin E Content 260 mg/g (387 IU/g)
Average MW ~ 1513
Waxy solid m.p. 37 - 41 C
Water-miscibility miscible in all parts
Solubility in PEG 400 miscible
HLB Value ~13.2
Liquid crystal structures solution gel
Stability in aqueous media stable at pH 4.5 - 7.5 hydrolyzed in the body
Vitamin E Content 260 mg/g (387 IU/g)
Milestones in the Development ofMilestones in the Development ofVitamin E TPGS NF forVitamin E TPGS NF for
Absorption Enhancement and Drug Delivery ApplicationsAbsorption Enhancement and Drug Delivery Applications
1950 Water-soluble vitamin E TPGS invented by Eastman Kodak Co. 1960 Suggested as a solubilizing agent for oil-soluble vitamins 1970 Toxicity and the effects on reproduction in rats studies 1980 Using TPGS for treating vitamin E deficient patients suggested
for treating chronic cholestasis demonstratedfor treating vitamin E deficiency in animals demonstrated
1990 Useful as a water-soluble antioxidant (effective after hydrolysis)Enhanced cyclosporin absorption demonstratedEnhanced vitamin D absorption demonstrated
1995 Mechanism of enhancing cyclosporin absorption suggestedLiquid crystalline properties characterized and reported
1996 TPGS as a P-glycoprotein inhibitor suggestedMany application patents appeared
1999 Amprenavir commercialized (semi-solid dosage forms)Vitamin E TPGS NF listed as an excipient in USP 24 (1999)
2000 Absorption enhancer for poorly absorbed drugs
Applications of Vitamin E TPGS NFin Drug Delivery Systems
Applications of Vitamin E TPGS NFin Drug Delivery Systems
1. Solubilize drugs2. Prevent drugs from crystallization3. Protect drugs in the absorption process4. Enhance bioavailability of poorly absorbed drugs5. Reduce drug sensitivity on skin or tissues6. A vehicle in a semi-solid dosage form7. Provide vitamin E or poorly soluble neutriceuticals in liquid
dosage form8. An emulsifier for injectable formulation9. A vehicle for pulmonary (inhalation) dosage form
10. A functional ingredient in self-emulsifying formulations11. A carrier for wound care and treatment12. A thermal binder in melt granulation/extrusion process
Melting Temperature of TPGSMelting Temperature of TPGS
00 2020 4040 6060
Temperature (C)Temperature (C)
10
. m
W1
0.
mW
1. 1st Heat Cycle2. 2nd Heat Cycle3. 10th Heat Cycle4. 20th Heat Cycle
1. 1st Heat Cycle2. 2nd Heat Cycle3. 10th Heat Cycle4. 20th Heat Cycle
114422
33
5050
Temperature (C)Temperature (C)
50. m
W50
. mW
Degradation Temperature = 200.0 CDegradation Temperature = 200.0 C
100100 150150 200200 250250
Thermal Stability of TPGSThermal Stability of TPGS
00
Heating Time (Minutes)Heating Time (Minutes)
5. m
W5.
mW
TPGS Under Sterilization Condition at 125 CTPGS Under Sterilization Condition at 125 C
1010 2020 3030 4040 5050
Stability of Vitamin E TPGS NF at 60CStability of Vitamin E TPGS NF at 60C
SampleSampleAcid
ValueAcid
ValueGardner
ColorGardner
Color
FreeTocopherol
(mg/g)
FreeTocopherol
(mg/g)
Potency,mg/g alphaTocopherol
Potency,mg/g alphaTocopherol
MeltingPoint,
C
MeltingPoint,
C
DegradationTemperature,
C
DegradationTemperature,
C
Time 0 0.30 4.3 5 262 40 210
Day 1 0.35 4.2 6 262 40 213
Day 3 0.31 4.2 5 255 40 215
Day 7 0.19 4.3 5 289 40 212
Vitamin E TPGS NF StabilityAmbient Stored as Packaged
Vitamin E TPGS NF StabilityAmbient Stored as Packaged
012357
1117
19
29
012357
1117
19
29
Time(mos.)Time
(mos.)
*d-alpha tocopherol content after saponification*d-alpha tocopherol content after saponification
0.60.60.60.80.80.60.90.7
0.8
1
0.60.60.60.80.80.60.90.7
0.8
1
AcidValueAcid
Value
2+3332+33+3+
2+
3
2+3332+33+3+
2+
3
GardnerColor
GardnerColor
290300292288290287292292
Not Tested
289
290300292288290287292292
Not Tested
289
Alpha Tocopherol(mg/g)*
Alpha Tocopherol(mg/g)*
75344564
4
3
75344564
4
3
FreeTocopherol
FreeTocopherol
700
600
500
400
300
200
100
035 40 45 50 55 60 65 70 75 80 85 90 95 100 105
Temperature, C
Viscosity*, centipoise
Melt Viscosity of Vitamin E TPGS NFMelt Viscosity of Vitamin E TPGS NF
*using Brookfield viscometer with spindle no. 21
656
485
374
303
240
155107 90 77
57
Thermal Properties of TPGSThermal Properties of TPGS
Melting temperature: 37 - 41CThermal degradation temperature: 200C
Stable under heat sterilization condition at 125Cfor at least one hour
Stable as a liquid at 60 - 75C for at least three daysStable as packaged at ambient storage conditions for more than 2 years
Low melt viscosity at ~ 75C for ease of handling
Melting temperature: 37 - 41CThermal degradation temperature: 200C
Stable under heat sterilization condition at 125Cfor at least one hour
Stable as a liquid at 60 - 75C for at least three daysStable as packaged at ambient storage conditions for more than 2 years
Low melt viscosity at ~ 75C for ease of handling
Surface Tension of TPGS at 37 CSurface Tension of TPGS at 37 C
TPGS Conc. (wt %)TPGS Conc. (wt %)0.00010.0001 0. 0010. 001 0. 010. 01 0.10.1
4040
4545
5050
5555
6060
6565
7070Surface Tension (dyne/cm)Surface Tension (dyne/cm)
CMC = 0.02 wt %CMC = 0.02 wt %
Volume FractionVolume Fraction00
00
Relative ViscosityRelative Viscosity
Relative Viscosity of TPGS in WaterRelative Viscosity of TPGS in Water
1010
2020
3030
4040
0.050.05 0.10.1 0.150.15 0.20.2 0.250.25
TemperatureTemperature20 C20 C25 C25 C30 C30 C35 C35 C40 C40 CHard SphereHard Sphere
Temp. (C)Temp. (C)Model R-Square = 96%, Root Mean Square Error = 4.8Model R-Square = 96%, Root Mean Square Error = 4.8
TPGS, %in WaterTPGS, %in Water
2020 2525 3030 3535 4040 45451010
1515
2020
2525
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
Viscosity, cpsViscosity, cps
Viscosity Behavior of TPGS/Water SystemViscosity Behavior of TPGS/Water System
11
% TPGS Monoester Remaining% TPGS Monoester Remaining
3030 6060 9090Time (Days)Time (Days)
WaterWaterWater/PGWater/PGpH 1.2pH 1.2pH 4.0pH 4.0pH 6.8pH 6.8
*Stored at 40 C, 75% RH*Stored at 40 C, 75% RH
00
2020