11.05.2015

The Properties and Functions of Vitamin E TPGS

Vitamin E polyethylene glycol succinate

Nigel Langley ExcipientFest 2015

Introduction

The need for solubilizers

Class II Class I

70% 5%

90%

Class IV Class III

Permeability 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”

Enhancement of solubility • pH-adjustment • co-solvents Class I • surfactant systems (incl. SEDDS) • complexation 5% • micronization / nano •… 90% Enhancement of permeability Enhancement of permeability • tight junction openers & • metabolic inhibitors • motility modifier Enhancement of solubility

Permeability • pro-drugs • efflux inhibitors (P-gp)

Solubility 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 succinate vitamin E (D-alpha tocopherol) glycol 1,000 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

Vitamin E polyethylene glycol succinate (USP) Names 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

Crystalli- Melting 20x zation 24h @ 20x 24h @ RT 65°C

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Kolliphor® TPGS resists stress

Keep for Cool down Melting 5 days and analyse at 80°C

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Thermal properties – Melting Point

30.0 400 TPGS was not pre-conditioned prior DSC measurement

350 25.0

300 20.0 250

15.0 200

cp (J/g*K) 150

10.0 Enthalpie (J/g)

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

25 • Thermally stable until 200°C • Flash point (DIN EN ISO 2592): 20 286°C • Inflammation point: 384°C 15

10 cp [J/gK]

5

0 15 35 55 Temperature [°C] MSDS:

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By the way – how does TPGS crystallize?

Cooling Decreasing from Volume outside to inside TPGS.mp4

Nuclei Nuclei growth formation on surface

Timelapse video wraps 5h into 20s 17.03.2015 10

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Kolliphor™ TPGS applications

Fields of Application

Enhancement of Excipient in Source of natural Bioavailability melt extrusion vitamin E

 Increase solubility of  Versatile plasticizer  For patients suffering poorly water-soluble with solubilization from vitamin E APIs properties malabsorption (cholestatic disease)*  Formulation of  Antioxidant for SEDDS sensitive excipients  Water-soluble vitamin E in dietary supplements

*GMP production according to ICH Q7 needed

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High Throughput Screening (HTS)

Analytics Automation UV/VIS, PSD 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% 2500

2000

1500

Solubility /ppm Solubility 1000

500 118 <5 <5 <5 <5 0 Carbamazepine Danazol Piroxicam Fenofibrate 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 APTIVUS AGENERASE 50 mg/ml oral solution oral solution soft gel capsules

 Each ml contains 50 mg  Tipranavir, protease  Amprenavir, of d-alpha-tocopherol, in inhibitor of HIV-1  The total amount of vitamin the form of tocofersolan,  Each milliliter of APTIVUS E in the recommended corresponding to 74.5 IU oral solution contains 116 daily adult dose of of tocopherol IU of vitamin E, and when AGENERASE is 1,744 IU. taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID results in a daily dose of 1160 IU.

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Products using Tocophersolan

Agenerase Viekira Pak Oral Solution 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 of amprenavir.  tablet contains 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  The maximum daily intake of TPGS is probably set by the vitamin E content 200 mg 200 mg 1-3 years (300 I.U.) (300 I.U.)  Recommended dietary allowance for 300 mg 300 mg vitamin E is quite low: 15 mg (~23 I.U.) 4-8 years (450 I.U.) (450 I.U.) for adults

600 mg 600 mg  However, the upper intake levels are 9-13 years (900 I.U.) (900 I.U.) much higher: 1,000 mg for adults irrespective of gender 800 mg 800 mg 14-18 years (1,200 I.U.) (1,200 I.U.)  This corresponds to a maximum daily intake of ~3.5 g for TPGS 1,000 mg 1,000 mg 19+ years (1,500 I.U.) (1,500 I.U.)

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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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