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The Properties and Functions of Vitamin E TPGS

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The Properties and Functions of Vitamin E TPGS 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 5/11/2015 2 1 11.05.2015 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 5/11/2015 3 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 5/11/2015 4 2 11.05.2015 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) 5/11/2015 5 Kolliphor® TPGS resists stress Crystalli- Melting 20x zation 24h @ 20x 24h @ RT 65°C 17.03.2015 6 3 11.05.2015 Kolliphor® TPGS resists stress Keep for Cool down Melting 5 days and analyse at 80°C 17.03.2015 7 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) 17.03.2015 8 4 11.05.2015 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: 17.03.2015 9 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 5 11.05.2015 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 5/11/2015 11 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 6 11.05.2015 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 5/11/2015 14 7 11.05.2015 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 5/11/2015 15 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) 5/11/2015 16 8 11.05.2015 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) 5/11/2015 17 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) 5/11/2015 18 9 11.05.2015 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) 5/11/2015 19 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 5/11/2015 20 10 11.05.2015 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 5/11/2015 21 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. 22 11 11.05.2015 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… 23 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.) 5/11/2015 24 12 11.05.2015 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 5/11/2015 25 13.
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