Excipients as Absorption Enhancers For Drug Delivery Applications

(A Case Study Using Vitamin E TPGS, NF)

Presented by

Stephen H. W. Wu, Ph.D Pharmaceutical Formulation Laboratory Eastman 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

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

Eastman Vitamin E TPGS NF

(d-Alpha Tocopheryl Polyethylene Glycol 1000 Succinate)
COO(CH2CH2O)nH (CH 2)2 O C O CH3 H3C CH3 O CH3 CH3 CH3 CH3 CH3

Key Attributes of Vitamin E TPGS

Average MW Waxy solid Water-miscibility Solubility in PEG 400 HLB Value Liquid crystal structures Stability in aqueous media Vitamin E Content

~ 1513 m.p. 37 - 41 C miscible in all parts miscible ~13.2 solution gel stable at pH 4.5 - 7.5 hydrolyzed in the body 260 mg/g (387 IU/g)

Milestones in the Development of Vitamin E TPGS NF for Absorption Enhancement and Drug Delivery Applications

1950 1960 1970 1980

Water-soluble vitamin E TPGS invented by Eastman Kodak Co. Suggested as a solubilizing agent for oil-soluble vitamins Toxicity and the effects on reproduction in rats studies Using TPGS for treating vitamin E deficient patients suggested for treating chronic cholestasis demonstrated for treating vitamin E deficiency in animals demonstrated Useful as a water-soluble antioxidant (effective after hydrolysis) Enhanced cyclosporin absorption demonstrated Enhanced vitamin D absorption demonstrated Mechanism of enhancing cyclosporin absorption suggested Liquid crystalline properties characterized and reported TPGS as a P-glycoprotein inhibitor suggested Many application patents appeared Amprenavir commercialized (semi-solid dosage forms) Vitamin E TPGS NF listed as an excipient in USP 24 (1999) Absorption enhancer for poorly absorbed drugs

1990

1995 1996 1999 2000

Applications of Vitamin E TPGS NF in Drug Delivery Systems

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Solubilize drugs Prevent drugs from crystallization Protect drugs in the absorption process Enhance bioavailability of poorly absorbed drugs Reduce drug sensitivity on skin or tissues A vehicle in a semi-solid dosage form Provide vitamin E or poorly soluble neutriceuticals in liquid dosage form An emulsifier for injectable formulation A vehicle for pulmonary (inhalation) dosage form A functional ingredient in self-emulsifying formulations A carrier for wound care and treatment A thermal binder in melt granulation/extrusion process

Melting Temperature of TPGS

10. mW

1. 2. 3. 4.

1st Heat Cycle 2nd Heat Cycle 10th Heat Cycle 20th Heat Cycle

3 2 4 1

20

40

60

Temperature (C)

Thermal Stability of TPGS

50. mW

Degradation Temperature = 200.0 C

50

100

150

200

250

Temperature (C)

TPGS Under Sterilization Condition at 125 C

5. mW

10

20

30

40

50

Heating Time (Minutes)

Stability of Vitamin E TPGS NF at 60C

Acid Value
0.30 0.35 0.31 0.19

Sample
Time 0 Day 1 Day 3 Day 7

Free Gardner Tocopherol (mg/g) Color

4.3 4.2 4.2 4.3 5 6 5 5

Potency, mg/g alpha Tocopherol

262 262 255 289

Melting Point, C
40 40 40 40

Degradation Temperature, C
210 213 215 212

Vitamin E TPGS NF Stability

Ambient Stored as Packaged
Time (mos.) 0 1 2 3 5 7 11 17 19 29 Acid Value 0.6 0.6 0.6 0.8 0.8 0.6 0.9 0.7 0.8 1 Gardner Color 2+ 3 3 3 2+ 3 3+ 3+ 2+ 3 Alpha Tocopherol (mg/g)* 290 300 292 288 290 287 292 292 Not Tested 289 Free Tocopherol 7 5 3 4 4 5 6 4 4 3

*d-alpha tocopherol content after saponification

Melt Viscosity of Vitamin E TPGS NF

Viscosity*, centipoise 700 656 600 500 400 300 200 100 0 35 485 374 303 240 155 107 90

77 57

40

45

50

55

60

65

70

75

80

85

90

95 100 105

Temperature, C *using Brookfield viscometer with spindle no. 21

Thermal Properties of TPGS

Melting temperature: 37 - 41C Thermal degradation temperature: 200C Stable under heat sterilization condition at 125C for at least one hour Stable as a liquid at 60 - 75C for at least three days Stable 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 C

70 65 60 55 50 CMC = 0.02 wt % 45 40 0.0001 Surface Tension (dyne/cm)

0. 001 0. 01 TPGS Conc. (wt %)

0.1

Relative Viscosity of TPGS in Water

40 Relative Viscosity
Temperature

30

20

20 C 25 C 30 C 35 C 40 C Hard Sphere

10

0 0 0.05 0.1 0.15 Volume Fraction 0.2 0.25

Viscosity Behavior of TPGS/Water System

Viscosity, cps
100 90 80 70 60 50 40 30 20 10 0 20 25 20 15 TPGS, %

in Water

25

30

35

40

Temp. (C)

10 45

Model R-Square = 96%, Root Mean Square Error = 4.8

Stability of TPGS in 10% Aqueous Solutions*

120 100 80 60 40 20 0
Water Water/PG pH 1.2 pH 4.0 pH 6.8

% TPGS Monoester Remaining

30

60

90

Time (Days)
*Stored at 40 C, 75% RH

Structure of Lipid Aggregates in Water

L1 La

L2

Hl

Hll

Phase Behavior of TPGS/Water Blends at 37 C

Increasing Water Content
Normal Micellar Phase Mixed Phase Hexagonal Mixed Reversed Mice- Lamellar Phase Phase llar Phase Phase

Properties Of TPGS In Water

TPGS is surface active CMC = 0.02 wt. % at 37 C TPGS is a good emulsifier TPGS in water forms liquid crystalline phases TPGS in water has a wide viscosity range TPGS is chemically stable in neutral aqueous media

Drug Absorption Mechanisms

How does TPGS enhance bioavailability of certain classes of poorly water-soluble or poorly absorbed drugs?

Effect of Water-soluble Vitamin E on Oral Cyclosporin2 in 10 Healthy Volunteers

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

FCYA + TPGS FCYA

1Vitamin

= 1.58 + 0.24

E TPGS 2.6 IU/kg 2Cyclosporin 10 mg/kg

Pathways of Intestinal Absorption

APICAL A B C D E F

C*

BASAL

A: B: C: D: E: F:

Paracellular diffusion Paracellular diffusion enhanced by a modulator of tight junctions Transcellular passive diffusion; C*: Intracellular metabolism Carrier-mediated transcellular transport Transcellular diffusion modified by an apically polarized efflux mechanism Transcellular vesicular transcytosis

Mechanisms of Drug Transport Across GI Absorptive Epithelia

Route Transcellular passive diffusion Examples Propranol Testosterone Ketoprofen Cisapride Estradiol Naproxen Cimetidine Loperamide Atenolol Mannitol Berberine Tiludronate

Paracellular passive diffusion

Mechanisms of Drug Transport Across GI Absorptive Epithelia

Route Carrier-mediated transcellular diffusion Examples Cephalexin Captopril Bestatin Levodopa Foscarnet Loracarbef Cyclosporin Nifedipine Verapamil Paclitaxel Celiprolol Digoxin Taxol

Transcellular diffusion subject to P-Glycoprotein efflux

Model of Drug Absorption in the Presence of Both P-Glycoprotein and Cytochrome P450 3A.

Drug

Pgp CYP3A D*

Model of P-Glycoprotein Substrate Absorption

a Ja-c Jc-a b Jb-a c inhib P-gp Jb-a

P-gp

Jb-c

Jc-b

Ja-b Ja-b < Jb-a

Ja-b Ja-b = Jb-a

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

Agenerase [Amprenavir (APV)]

(Lawrence Yu et. al, Pharm. Res. 16(12), p. 1812, 1999) A HIV protease inhibitor, used in AIDS therapy The current clinical approach to HIV therapy utilizes a combination regimen consisting of a protease inhibitor with other reverse transcriptase inhibitors APV has a low solubility in water and is poorly wetted Conventional oral formulations (capsules and tablets) had no detectable drug in the blood after administration The current estimate of the daily dose is high (1200 mg/b.i.d.)

Structure and pH-Solubility of Amprenavir Free Base

1.0 1.0

NH2 HN S N OH

Solubility (mg/mL)

O O O

O O H3C

CH3

0.1

0.1

pKa = 1.97
0.01 0 1 2 0.01 3 4 5 6 7 8 9 10 11 12 13 14 pH

Solubility Data Analysis and Results

APV + (TPGS)m Sbound
Solubility (mg/mL)

APV - (TPGS)m
0.15 0.12 0.09 0.06 0.03 CMC = 0.20 mg/mL 0.00 0.0 0.5 1.0 1.5 2.0 Vitamin E-TPGS (mg/mL)

ka =

Sfree (TPGS)m

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

Permeability Results
(Caco-2 Cell Model)
Apparent permeability x 106 (cm/sec) 14 12 10 8 6 4 2 0 0 0.0002 0.002 0.02 0.2 2

TPGS concentration (mg/mL)

Absorption Flux for Amprenavir

0.9
Absorption flux (mg/cm2/sec x 10-6)

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.5 0.5 1.0 TPGS concentration (mg/mL) 2.0

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

Examples of TPGS Applications in Patent Art

1954 1963 1987 1993 Solubilizing agent Emulsifying agent Application utilizing compatibility with nasal mucosal membrane Cytoprotective agent Improved bioavailability Powder formulation Topical treatment of sunburn Coating additive Solubilizing poorly water-soluble drugs (transmucosal) Skin treatment Ophthalmic formulations Topical homeostatic application Oral insulin delivery Drug delivery using liquid crystalline structures Specific absorption enhancement applications

1994 1995 1996 1997 1998 1999 2000