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