Vitamin E TPGS Story

Life Cycle of a New Excipient

From Discovery, to Development, to Launch

(A Case Study of Vitamin E TPGS, NF)

Presented by

Stephen H. W. Wu, Ph.D

Former Organization: Pharmaceutical Formulation Laboratory,

Eastman Chemical Company

Present Organization: Pharmaceutical R/D

Covidien

The approach taken in this

presentation

Milestones of developing Vitamin E TPGS NF

as a new excipient.

Examine characteristics of each phase from

discovery, to development, and to launch

Hurdles – customer’s perspective and

supplier’s perspective

Challenges for innovating new excipients

(CH2)2

C

O

O

COO(CH2CH2O)nH

CH3

CH3

H3C O

CH3

CH3 CH3

CH3

CH3

Vitamin E TPGS 1000 NF (d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate)

A Functional Excipient for Improving Drug

Bioavailability

Other derivatives – dl- TPGS 1000, d-TPGS 400, 200,

Milestones in the Discovery Phase

• 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 studied

• 1980 TPGS used for treating vitamin E deficient patients, chronic cholestasis, and vitamin E deficiency in animals.

• 1990 Useful as a water-soluble antioxidant (effective after hydrolysis)

Enhancing absorption of cyclosporine and vitamin D reported

• 2000 Accepted and known as a pharmaceutical solubilizer and absorption enhancer.

0

Days

10 20 30 40 50 60 70 80 90 100 110 1200.0

0.2

0.4

0.6

0.8

1.0

1.2

Tocopherol,

Oil

62 IU/kg

WashoutWashout

TPGS,

6.6 IU/kg

WashoutAcetate Water

Dispersible

62 IU/kgBaseline

Seru

m a

-to

co

ph

ero

l, m

cg

/ml

Studies on the Vitamin E Nutrition of ElephantsDenver Zoological Gardens

B - SWUE D-11B 22

TPGS

5,250

IU/day

Washout

TPGS

2,100

IU/dayWashout

2,100

IU/day2,000

IU/day

31,500

IU/day

d-a-tocopheryl

acetatedl-a-t

oco

ph

ery

l

aceta

te

0 1 2 3 4 5 6 7 8 9 10 11 12

Week

0.0

0.20.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6

2.8

3.0P

las

ma

a-t

oc

op

he

rol, m

cg

/ml

Study on the Vitamin E Nutrition of the Black Rhino

Miami Metro Zoo

B - SWUE D-11B 23

Bioavailability of Vitamin E in Horses

0

0.4

0.8

1.2

1.6

2

After 5 Days After 35 Days

dl-a-tocopheryl acetate (solid water dispersible)

d-a-tocopheryl acetate (solid water dispersible)

TPGS

TPGS + d-a-tocopheryl acetate

Inc

rea

se

on

Pla

sm

a O

ve

r

Bas

eli

ne

, m

cg

/ml

B - SWUE D-11B 21

Characteristics of Discovery Phase

Supplier suggested that vitamin E TPGS could function as a “Bioenhancer”

Very limited material property data

Lack of biopharmaceutical mechanistic understanding

Literature reports about treating Vitamin E deficient syndromes using TPGS

Exotic “animal study” results

Customers willing to try because of curiosity, or looking for new excipient functionalities, and perceiving TPGS is safe to use.

Very few patents related to TPGS

Transforming from a nutrition supplement to excipient applications

Milestones in the Development Phase

• 1995 Mechanism of enhancing cyclosporine absorption discussed in literature

TPGS Material Properties reported

- Thermal properties and thermal stability

- Solution properties

- Liquid crystalline properties

Biopharmaceutical drug classification (BCS) System

initiated, and increasingly used and discussed

• 1996 TPGS as a P-glycoprotein inhibitor suggested

• 1998 Biopharmaceutical studies for TPGS family usingCaco 2 cells initiated by the supplier

Melting Temperature of TPGS

0 20 40 60

Temperature (°C)

10. m

W

1. 1st Heat Cycle

2. 2nd Heat Cycle

3. 10th Heat Cycle

4. 20th Heat Cycle

1

4

23

50

Temperature (°C)

50

. m

W

Degradation Temperature = 200.0 ºC

100 150 200 250

Thermal Stability of TPGS

Stability of Vitamin E TPGS NF at 60°C

Sample

AcidValue

GardnerColor

FreeTocopherol

(mg/g)

Potency,mg/g alphaTocopherol

MeltingPoint,

°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

012357

1117

19

29

#

Time(mos.)

*d-alpha tocopherol content after saponification

# Stability unchanged after 48 months

0.60.60.60.80.80.60.90.7

0.8

1

AcidValue

2+3332+33+3+

2+

3

GardnerColor

290300292288290287292292

Not Tested

289

Alpha Tocopherol(mg/g)*

75344564

4

3

FreeTocopherol

700

600

500

400

300

200

100

0

35 40 45 50 55 60 65 70 75 80 85 90 95 100 105

Temperature, °C

Viscosity*, centipoise

Melt Viscosity of Vitamin E TPGS NF

*using Brookfield viscometer with spindle no. 21

656

485

374

303

240

155107 90 77

57

Surface Tension of TPGS at 37 °C

TPGS Conc. (wt %)

0.0001 0. 001 0. 01 0.140

45

50

55

60

65

70Surface Tension (dyne/cm)

CMC = 0.02 wt %

Volume Fraction

00

Relative Viscosity

Relative Viscosity of TPGS in Water

10

20

30

40

0.05 0.1 0.15 0.2 0.25

Temperature

20 °C25 °C30 °C35 °C40 °CHard Sphere

1

% TPGS Monoester Remaining

30 60 90

Time (Days)

WaterWater/PGpH 1.2pH 4.0pH 6.8

*Stored at 40 °C, 75% RH

0

20

40

60

80

100

120

Stability of TPGS in 10% Aqueous Solutions*

Hydrolysis of Vitamin E TPGS 1000 NF in Buffers

0

5

10

15P

erce

nt H

ydro

lysi

s

0 50 100 150

Tim e (Hours)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Per

cen

t Hyd

roly

sis

0 50 100 150

Tim e (Hours)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Per

cen

t Hyd

roly

sis

0 50 100 150

Tim e (Hours)

pH 1.2 pH 4.5

pH 6.8Model of Hydrolysis Rate at pH 1.2, 37 oC

%Hydrolysis = 0.0954xTime (hrs) – 0.0758

37 o C

25 o C

5 o C

<<<CLICK CENTER OF IMAGE TO RETURN>>> 100% TPGS 60x.JPG

<<<CLICK CENTER OF IMAGE TO RETURN>>> 20-80 60x relaxed.JPG

<<<CLICK CENTER OF IMAGE TO RETURN>>> 60-40 60x.JPG

Birefringence of

TPGS/water

mixtures

Increasing TPGS concentration in water

Structure of Lipid Aggregates in Water

L1

La

L2

HlHll

Normal Mice-

llar Phase

Mixed

Phase

Hexagonal

Phase

Mixed

Phase

Reversed Mice-

llar Phase

Lamellar

Phase

Increasing Water Content

Phase Behavior of TPGS/Water Blends at 37 °C

Example of Enhancing Taxol Solubility

Experiment -• The solubility of taxol was measured in the permeability assay buffer with and

without 0.1% of d-TPGS 1000

• Excess taxol powder was introduced to each solution. The samples were then

agitated (vortexed) for 2-hours and left to stand overnight at room temperature.

• The samples were then filtered using a 0.45 M nylon membrane syringe filter

and assayed using LC/MS.

• The concentration in the filtrate is taken to be the equilibrium solubility in each

matrix as shown below

Results –

Solution Solubility (mg/mL)

Buffer (pH 7.0) without TPGS 2.2x10-4

Buffer (pH 7.0) with 0.1% TPGS 3.9x10-3

Key Attributes of Vitamin E TPGS NF

Average MW ~ 1513

Waxy solid m.p. 37 - 41 °C

Water-miscibility miscible in all parts

Solubility in PEG/PG (1:1) soluble

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)

Drug Absorption Mechanisms

How does TPGS enhance bioavailability of

certain classes of poorly water-soluble or

poorly absorbed drugs?

Clinical Evaluation – Literature Example

1Vitamin E TPGS 2.6 IU/kg (1.75 mg/kg)2Cyclosporine A 10 mg/kg

= 1.58 + 0.24FCYA + TPGS

FCYA

Effect of Water-soluble Vitamin E1 on Oral Cyclosporine2 in

10 Healthy Volunteers

(Chang, Benet & Hebert, Clin. Pharmacol. Ther. 59:297-303, 1996.)

A B C D E F

CC* E

A B C D E F

Pathways of Intestinal Absorption

APICAL

BASAL

A: Paracellular diffusion

B: Paracellular diffusion enhanced by a modulator of tight junctions

C: Transcellular passive diffusion; C*: Intracellular metabolism

D: Carrier-mediated transcellular transport

E: Transcellular diffusion modified by an apically polarized efflux mechanism

F: Transcellular vesicular transcytosis

Model of P-Glycoprotein Substrate Absorption

Ja-c Jc-a Jb-a Jb-a

Jb-c Jc-b Ja-b Ja-b

P-gp

inhib

P-gp

a b c

Ja-b < Jb-aJa-b = Jb-a

(J. Hunter, B. H. Hirst / Advanced Drug Delivery Reviews 25 (1997) 129-157)

Markers for Permeability Study

A. Propranolol Transcellular

B. Atenolol Paracellular

C. Lucifer Yellow Paracellular (Low permeability)

D. Digoxin P-glycoprotein substrate

E. Taxol P-glycoprotein substrate

Effects of TPGS on Permeability of Control

Compounds Using Caco-2/TC7 Cell Model

Lucifer Yellow 0.09 0.13 NA

Atenolol 0.11 0.14 NA

Propranolol 16.5 11.6 NA

Digoxin 1.89 9.57 7.0

Taxol 3.09 33.1 10.7

Papp x10-6 cm/s Papp x10-6 cm/s

Compound A- to-B B-to-A Ratio

PappB-A

PappA-B

No TPGS

Effects of TPGS on Permeability of Actives

Using Caco-2/TC7 Cell Model

Lucifer Yellow 0.09 0.13 NA

Atenolol 0.11 0.14 NA

Propranolol 16.5 11.6 NA

Digoxin 1.89 9.57 7.0

- TPGS (0.01%) 1.94 3.12 1.6

- TPGS (0.10%) 1.90 2.36 1.2

Taxol 3.09 33.1 10.7

- TPGS (0.01%) 1.97 14.7 7.5

- TPGS (0.10%) 0.55 3.19 5.8

Papp x10-6 cm/s Papp x10-6 cm/s

Compound A- to-B B-to-A Ratio

PappB-A

PappA-B

Characteristics of Development Phase

• Supplier began to generate pre-formulation data to help customers – “interactive” in nature

• Supplier also took an active role to characterize material properties and suggested new applications.

• Increasing biopharmaceutical mechanistic understanding

– TPGS is a p-gp inhibitor

• Patents relating to TPGS started to show up

Data suggested that TPGS could be used as a solubilizer and absorption enhancer

Milestones in the Launch Phase

• 1999 Amprenavir commercialized by GSK (semi-solid dosage forms) with supporting data published

Vitamin E TPGS NF listed as an excipient in USP 24 (1999)

• ~ 2000 Increasing needs for solubilizers and absorption enhancers for many poorly absorbed drugs

• 2002 New neutraceutical and OTC products launched

• 2003 Registration in countries such as in Greater China

“Generic” competitions began

SO

O N

H3C

CH3

HN OO

O

OH

NH2

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

pH

0.01

0.1

1

1.0

0.01

0.1

1

1.0

So

lub

ilit

y (

mg

/mL

)

Structure and pH-Solubility of

Amprenavir Free Base

pKa = 1.97

CMC = 0.20 mg/mL

0.15

0.12

0.09

0.06

0.03

0.00

0.0 0.5 1.0 1.5 2.0

Vitamin E-TPGS (mg/mL)

So

lub

ilit

y (

mg

/mL

)

APV + (TPGS)m APV - (TPGS)m

ka =Sbound

Sfree • (TPGS)m

Stotal = Sfree + Sbound

Stotal = Sfree [1 + ka (TPGS)m]

Solubility Data Analysis and Results

Permeability Results(Caco-2 Cell Model)

14

12

10

8

6

4

2

0

0 0.0002 0.002 0.02 0.2 2

TPGS concentration (mg/mL)

Ap

pare

nt

perm

eab

ilit

y x

10

6(c

m/s

ec)

Absorption Flux for Amprenavir

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Ab

so

rpti

on

flu

x (

mg

/cm

2/s

ec x

10

-6)

0.50.0 1.0 1.5 2.0

TPGS concentration (mg/mL)

1. Below the cmc, Vitamin E TPGS has no effect on the solubility of

amprenavir, but above the cmc, the solubility linearly increases with

TPGS concentration (approximately 10 TPGS molecules required for

one amprenavir molecule).

2. Amprenavir showed polarized transport across Caco-2 cells;

Permeability (BL –>AP) > Permeability (AP –>BP) by six fold. These

two rates were about equal when TPGS concentration is about 0.2

mg/mL.

3. The absorption flux (permeability x solubility) increases with increasing

TPGS concentration. The softgel formulation containing 20 % TPGS

gives 69 8 % absolute bioavailability in beagle dogs after a 25 mg/Kg

dose. Increasing TPGS from 20 – 50 % in the formulation improved the

absolute bioavailability to 80 16 %. These in vivo data are in

agreement with absorption flux by permeability measurement.

TPGS Enhances Bioavailability of Amprenavir[Lawrence Yu, et. al., Pharm. Res. 16 (12), 1812 (1999)]

Role of TPGS in Improving

Bioavailability of Amprenavir

• The solubility of Amprenavir was improved in the

presence of TPGS through micellar

solubilization

• TPGS also enhances the permeability of

Amprenavir

• Overall, TPGS enhanced the absorption flux of

Amprenavir by increasing its solubility and

permeability

BiopharmaceuticalMechanism

TPGS improves drug solubility and Caco 2 cell permeability.

TPGS is a P-gp inhibitor.

TPGS brings drug molecules to membrane surface, modify membrane fluidity, and inhibits efflux.

The interaction is transient and reversible.

Drug

D

D*

CYP3A

Pgp

Drug TPGS

TPGS in formulations

Commercial Products

Using Vitamin E TPGS 1000 NF

Solubilizer- AgeneraseTM GlaxoSmithKline

- NurofenTM Boots Healthcare

- Wal-ProfenTM Walgreens

- BioResponse–DIMTM BioResponse L.L.C. (Diindolylmethane)

Vitamin E supplement

- Poly-vi-solTM BMS

- VidailynTM Abbott

- LIQUI-E Twinlab

Applications* of Vitamin E TPGS NF

in Drug Delivery Systems

1. Solubilize drugs

2. Prevent drugs from crystallization

3. Protect drugs in the absorption process

4. Enhance bioavailability of poorly absorbed drugs or

nutraceuticals

5. Reduce drug toxicity, or sensitivity on skin or tissues

6. A vehicle in a semi-solid dosage form

7. An emulsifier for injectable formulations

8. A functional ingredient for inhalation dosage form

9. A functional ingredient in self-emulsifying formulations

10. A carrier for wound care and treatment

11. A thermal binder in melt granulation/extrusion process

12. A carrier for actives enhancing sexual pleasure

Examples of TPGS Applications in Patent Art

1954 Solubilizing agent

1963 Emulsifying agent

1987 Application utilizing compatibility with nasal mucosal membrane

1993 Cytoprotective agent

Improved bioavailability

Powder formulation

Topical treatment of sunburn

1994 Coating additive

1995 Solubilizing poorly water-soluble drugs (transmucosal)

1996 Skin treatment

Ophthalmic formulations

1997 Topical homeostatic application

1998 Oral insulin delivery

1999 Drug delivery using liquid crystalline structures

2000+ Specific absorption enhancement applications

Characteristics of Launch Phase

TPGS functions supported by products and literature

New applications began to evolve

Evidence led to better understanding of absorption mechanism

Increasing patent activities relating to TPGS

TPGS is a functional excipient for enhancing drug solubility and absorption

Critical Issues (Hurdles) for Developing

A New Excipient (Absorption Enhancer)

Cost, volume and rewards

Supporting data

Preformulation

Formulation

Biopharmaceutical

Effectiveness and safety

Quality and manufacturing

Patents

Regulation - a drug or an excipient?

Challenges for Developing a New Excipient

• Seeking novel functionalities of “safe”

materials

• Changing physical forms or combinations

of existing materials

• Minor chemical modification of existing

excipients

• Smart materials to meet specific needs

• Suppliers and customers must work

together