Journal of Pharmaceutical Investigation DOI 10.1007/s40005-016-0300-x

Online ISSN 2093-6214 Print ISSN 2093-5552

REVIEW

Application of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in transdermal and topical drug delivery systems (TDDS) Cuong Viet Pham1 · Cheong-Weon Cho1 

Received: 31 October 2016 / Accepted: 26 December 2016 © The Korean Society of Pharmaceutical Sciences and Technology 2017

Abstract D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble nonionic surfactant, which is prepared from the esterification of Vitamin E succinate with polyethylene glycol 1000. Due to unique amphiphilic structure, TPGS offers many essential properties such as solubilizer, penetration enhancer, stabilizer, emulsifier, antioxidant agent and protection of drug in micelles, which can be used for permeation of drug through skin or deposition of drug in skin. Especially, the applications of TPGS for various systems such as supersaturated system, solid lipid nanoparticles, gels, microemulsions, nanoemulsions and solid dispersions will be discussed in this review. Keywords

TPGS · Solubilizer · Transdermal · Topical

Introduction Rapid advances in pharmaceutical technologies have given the formulation scientists many opportunities to explore alternative routes for the delivery of drug safely, efficiently, and effectively to the targeted site (Singh et al. 2016; Heather and Adam 2012). Two of the routes gaining increasing attentions are transdermal and topical drug delivery systems (TDDS) due to the advantages over conventional oral and invasive methods of drug delivery (Marwah et  al. 2016). Several important advantages of transdermal route are (1) to avoid degradation of drug in the stomach environment (2) to bypass the hepatic first

* Cheong-Weon Cho [email protected] 1

College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea

pass metabolism (3) to be administered for long-term therapy in case of the drug with short half-life (4) to reduce side effects such as gastric irritation by non-steroidal antiinflammatory drugs (5) to be controlled within a precise therapeutic window, and (6) to enhance patient compliance (Marwah et al. 2016; Heather and Adam 2012; Kydonieus and Berner 1987). On the other hand, the topical delivery to the skin rather than through the skin (transdermal delivery) has additional advantage of better physiological and pharmacological response of drug at the target site (Singh et al. 2016; Heather and Adam 2012). D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, Fig.  1) has an amphiphilic structure. It was composed of lipophilic alkyl tail from nonracemic vitamin E and hydrophilic polar head from polyethylene glycol (PEG) 1000 with a hydrophilic/lipophilic balance value of 13.2 and critical micelle concentration (CMC) of 0.02% w/w. It forms as a waxy solid with melting point of about 37–41 °C (Guo et al. 2013; Wu and Hopkins 1999). TPGS was listed up in United States Pharmacopeia (USP) 32-National Formular (NF) 27 (Table 1). Recently, TPGS is gaining interests in drug delivery systems as a penetration enhancer, wetting agent, emulsifier, solubilizer, spreading agent, protector and detergent (Neophytou et al. 2014; Guo et al. 2013; Suppasansatorn et  al. 2007). Some pharmaceutical products used TPGS in the formulations such as capsules (PDR 2005), tablets (Crowley et al. 2002), hot-melt extrusion (Repka and McGinity 2000), microemulsions (Suppasantorn et al. 2007), topical products (Sheu et al. 2003), and parenterals (Constantinides et al. 2004). TPGS has useful properties such as solubilization enhancement, permeation enhancement, stabilization the system by hydrophobic interactions, contribution of the level of lipophilicity in the skin, and function of incorporation of drug in micelles formed at concentrations over

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C. V. Pham, C.-W. Cho

Fig. 1 Chemical structure of TPGS (Guo et al. 2013)

Table 1 Pharmacopeial specification of TPGS Test

USP32-NF27

Identification Solubility in water Acid value Specific rotation Assay (α-tocopherol)

+ + + ≥+24.0 ≥25.0%

CMC (Suppasansatorn et  al. 2007; Yan et  al. 2007; Sheu et al. 2003, 2006; Mohammed 2001). In this review, the applications of TPGS in transdermal and topical formulation will be discussed carefully.

Supersaturated system Supersaturated formulation has several advantages for topical and transdermal drug administration, namely: (1) enhancing driving force, which enables molecules to better penetrate through the stratum corneum (SC); (2) penetration enhancement without using chemical penetration enhancers; (3) concentration reduction, particularly for very potent or expensive drugs (e.g., fentanyl). Supersaturated solutions in transdermal drug delivery was first studied by Higuchi in 1960 (Heather and Adam 2012). Then, several studies used supersaturated systems for increasing the permeability of drug through the skin (Ghosh and Michniak-Kohn 2012a). Davis and Hadgraft have shown supersaturated systems resulted in linear flux proportional to their degree of supersaturation (Davis and Hadgraft 1991). However, since the thermodynamic activity of supersaturated systems is higher than that of saturated systems, thus the drug expresses the tendency to nucleate immediately after preparing or even during storage. When the drug precipitates, its transport flux becomes independent from the concentration and the release becomes no longer a zero order. These prevent the production of

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supersaturated systems and their storage for long time (Ghosh and Michniak-Kohn 2012a; Heather and Adam 2012). To overcome this matter, formulation scientists produced supersaturated formulation using polymers or solubilizers with the purpose of systems stabilization. Therefore, polymers and solubilizers are very important to formulate a stable supersaturated matrix. In the publication of Ghosh and co-worker, the authors systematically investigated different solubilizers/co-solvent for producing supersaturated systems by abrupt change of solubility of poorly water-soluble drug (Ghosh and Michniak-Kohn 2012a). Propylene glycol (PG) was employed as a co-solvent, whereas TPGS and poloxamer 407 were used as non-ionic solubilizers to improve the solubility of ibuprofen. To inhibit crystal growth, polymeric stabilizers such as hydroxylpropyl methylcellulose (HPMC) of 3 cps and polyvinylpyrrolidone (PVP) K-30 were also utilized. In presence of PG, significant growth of ibuprofen crystals was observed within 6  h. Also, when TPGS and poloxamer 407 were added to formulations, crystal growth was also appeared. However, the sizes of ibuprofen crystals were comparatively smaller. Especially, in presence of HPMC, crystal growth was inhibited for ibuprofen-PG system. Interestingly, by the use of TPGS and poloxamer 407, ibuprofen crystals were significantly inhibited and also the size of the crystals were smaller in comparison with those observed with PG (Fig.  2) (Ghosh and MichniakKohn 2012a). This result was also consisted that TPGS and poloxamer 407 produced a supersaturated drug concentration for a poorly water-soluble weakly basic drug (Li et al. 2012). In vitro permeation study using silicone membrane, the highest permeated flux was observed for TPGS system followed by poloxamer 407 and finally PG (Fig.  3). When the silicone membrane was replaced by porcine skin, the transport flux expressed similar trends, with the highest permeability seen with TPGS. The permeation flux was determined for these formulations using Fick’s first law. Fick’s first law: J = DKC/h where J is the flux across a ratelimiting barrier thickness (h) at sink conditions including solubility (C), lipophilicity (partition coefficient, K), and the molecular weight or size (diffusion coefficient, D). Theoretically, the formulation containing PG should have shown the highest flux due to higher thermodynamic activity resulting from higher solubility of ibuprofen in comparison with TPGS. This opposite result may be elucidated by the following reasons. Besides solubility enhancement, TPGS also plays an important role in facilitating diffusion by modifying the skin structure (D), by improving partition coefficient by making the barrier more lipophilic (K) and thus, finally, reducing the interfacial tension. This changes the properties of the SC into being more permeable to poorly-water soluble compounds as ibuprofen. Hence,

Application of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in transdermal… Fig. 2 Microscopic study of crystal growth in supersaturated solutions after 1 week A-Drug, B-Drug + PG, C-Drug + TPGS, D-Drug + Poloxamer, E-Drug + PG + HPMC, F-Drug + PG + PVP, G-Drug + TPGS + HPMC, H-Drug + TPGS + PVP

Fig. 3 Enhancement rate of flux of ibuprofen in supersaturated containing solubilizing agent systems compared to supersaturated system without solubilizing agent through silicone membrane and porcine skin according to different solubilizing agents

this can be explained why the flux enhanced through the skin for TPGS. In addition, TPGS also probably assisted the drug to remain in the supersaturated state by hydrogen bonding with the molecule of ibuprofen (Ghosh and Michniak-Kohn 2012a) (Table 2).

Submicron particles and nanoparticles According to this current classification system, the particles (their size is less than 1  mm) are divided into three groups: nanoparticles (less than 100  nm), submicron particles (100 nm–1  µm) and microparticles (1  µm–1  mm) (Ghosh and Michniak-Kohn 2012b; Bolzinger et al. 2011).

When micro- and nanotechnology have been developed, application of these modern technologies for transdermal drug delivery enhancement has been considered more. There have been many different approaches to prepare formulation such as microparticles, solid lipid nanoparticles, and nanostructured lipid carriers were also evaluated (Baek et  al. 2015; Ghosh and Michniak-Kohn 2012b; Jana et  al. 2009; Müller et al. 2002). Decreasing the particle size of a compound to the submicron range results in increased its saturation solubility, increased dissolution velocity and increased adhesion. This increase probably promoted the permeation enhancement through the skin due to an enhanced concentration gradient between donor and receptor compartments (Fig.  4)

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C. V. Pham, C.-W. Cho Table 2 Summary of some applications of TPGS in TDDS Formulations

Drugs

Adminitration routes (transdermal or topical)

Roles of TPGS in formulations

Membranes used in permeation study

Permeation/retention enhancement as compared to control samples

References

Supersaturated solutions

Ibuprofen

Transdermal

Solubilizer

+

Ibuprofen

Transdermal

Solubilizer

Silicone membrane, porcine skin Porcine skin

+

Cyclosporin A

Transdermal

Stabilizer

Pig ear skin

+

Ghosh and Michniak-Kohn (2012a) Ghosh and Michniak-Kohn (2012b) Romero et al. (2016)

Penetration enhancer Emulsifier, stabilizer, antioxidant Penetration enhancer Solubilizer

Human-derived epidermis Dorsal skin of mice Abdominal rat skin Porcine skin, human skin

++

Solubilizer, permeation enhancer, retention enhancer Solubilizer, permeation enhancer, retention enhancer Permeation enhancer, retention enhancer Retention enhancer

Submicron particles and nanoparticles

Kaempferia Parviflora extracts Quercetin

Transdermal, topical Transdermal, topical Diclofenac sodium Transdermal

Gel and nanogel

Micro- and nanoemulsions

Ibuprofen

Transdermal

Griseofulvin

Transdermal, topical

Amphotericin B

Transdermal, topical

Temozolomide hexyl ester prodrug Paclitaxel

Transdermal, topical

Genistein

Topical

Progesterone, α-tocopherol, lycopene Estradiol

Transdermal, topical

Minoxidil Aceclofenac, Capsaicin Other applications

Minoxidil Nicotine Estradiol Progesterone

+ enhancement, − reduction

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Topical

Transdermal, topical Transdermal, topical Transdermal, topical Topical, transdermal Transdermal, topical Transdermal Transdermal

++

Sutthanut et al. (2009) Zhu et al. (2016)

No effect

Mohammed (2001)

+

Abdominal skin of ++ Laca mice

Ghosh and Michniak-Kohn (2013) Aggarwal et al. (2012)

Porcine ear skin

++

Kaur et al. (2015)

Silicon membrance, rat skin

++

Suppasansatorn et al. (2007)

Rat skin

+

Emulsifier, antioxidant Emulsifier

Mixed Cellulose Ester membrane Porcine ear skin

+

Khandavilli and Panchagnula (2007) Brownlow et al. (2015) Carvalho et al. (2016)

Solubilizer

Mice SC

Solubilizer, reten- Mice skin tion enhancer Emulsifier, penHuman skin, etration enhancer inflamed mice skin Solubilizer, reten- Mice skin tion enhancer Solubilizer, penPorcine ear skin etration enhancer Solubilizer Mouse skin Solubilizer Mouse skin

++

Liou et al. (2009) −+

Sheu et al. (2006)

++

Somagoni et al. (2014)

+−

Chen et al. (2005)

++

Borgheti-Cardoso et al. (2016) Sheu et al. (2003) Falconer et al. (2014)

− +

Application of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in transdermal… Fig. 4 Mechanisms of increased penetration of micronized drug particles vs. drug nanoparticles. Upper increased concentration gradient leads to increased flux into the skin. Lower more even distribution in combination with higher saturation solubility Cs leads to more even concentration gradient between formulation and skin

(Romero et  al. 2016; Ghosh and Michniak-Kohn 2012b). Recently, some compounds such as rutin, hesperidin, resveratrol and ascorbyl palmitate, which are all poorly soluble ingredients were cosmetically employed according to this formulation principle (Mishra et  al. 2009; Kobierski et  al. 2009). However, besides particle size, skin absorption was also impacted strongly by the type of excipients employed in the formulation. The uptake of drug particles requires adequate wetting and thus the presence of solubilizers/surfactants plays an important role in penetration enhancement (Ghosh and Michniak-Kohn 2012b). Although there have been many studies about TPGS to improve the oral bioavailability of drugs (Rajebahadur et  al. 2006; Varma and Panchagnula 2005), but many reports were not published to investigate its effect on the

skin delivery (Ghosh and Michniak-Kohn 2012b). Hence, Ghosh and co-worker studied the effect of different solubilizers/co-solvents such as TPGS, poloxamer 407and PG on the permeability of ibuprofen in suspension having a submicron particle size with or without two different polymeric stabilizers HPMC and PVP K-30. The results showed that permeation rate of ibuprofen was always the highest for formulations (submicron suspension or non-micronized suspension) containing TPGS, followed by poloxamer 407 and PG (Fig. 5). In addition, it was observed that the influence of solubilizers on the permeability enhancement appeared to be equally critical in comparison with the nanosizing process and TPGS was found to be the most effective permeation enhancer (Ghosh and Michniak-Kohn 2012b).

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C. V. Pham, C.-W. Cho Before micronizaƒon

Flux of ibuprofen through porcine skin (µg/cm²/h)

Fig. 5 Flux of ibuprofen in suspensions before micronization and suspensions after micronization through the porcine skin according to different solubilizing agents

A…er micronizaƒon

60 50 40 30 20 10 0 None

PG

TPGS

Poloxamer 407

Solubilizing agent

Other group of scientists formulated amorphous cylosporin A (CyA)-loaded nanoparticles suspension using TPGS as a stabilizer to increase dermal penetration through pig ear skin. The CyA nanoparticles and µm-sized CyA particles were incorporated into hydroxypropylcellulose gels and the penetration study was applied using the tape stripping method. After repeated taping, the cumulative permeated amount of CyA from nanoparticles was 6.3 times higher compared to the µm-sized raw drug powder (450.1 vs 71.3 µg/cm²) (Romero et al. 2016). Zhu et  al. showed that quercetin-loaded poly lactic-coglycolic acid (PLGA)-TPGS nanoparticles could overcome low hydrophilicity of quercetin and increase its anti-ultraviolet B (UVB) effect. Quercetin-loaded PLGA-TPGS nanoparticles can significantly block UVB irradiation. Moreover, PLGA-TPGS nanoparticles could efficiently penetrate through epidermis and reach dermis layer. The quercetin retained in SC was less significant in comparison with that in epidermis/dermis layers. The results demonstrated that PLGA-TPGS nanoparticles could be employed as skin drug delivery carriers (Zhu et al. 2016) (Table 2). Solid liquid nanoparticles (SLNs) have been reported as promising carrier systems for cosmetics and topical products due to the following advantages (Sutthanut et al. 2009; Souto et al. 2004; Alonso 2004); (1) protection of the active agent against chemical degradation, e.g., retinol (Jenning et al. 2000), tocopherol and coenzyme Q10 (Nehilla et al. 2008); (2) modification of the release profile of the active ingredient (Souto et  al. 2004; Müller and Dingler 1996); (3) providing an occlusive effect resulting in skin hydration (Souto et  al. 2004; Wissing and Müller 2002, 2003; Lippacher et  al. 2001; Cevc and Blume 1992); (4) photoprotection effects (Wissing and Müller 2002); and (5) enhancement of drug penetration into the mucosa or skin (Elsayed et  al. 2007; Axelsson 1989). The topical formulation of Kaempferia parviflora (KP) crude extracts containing TPGS using SLNs prepared by the nano-template

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engineering method (Sutthanut et  al. 2009). The formulation containing 1.6 mg/mL stearyl alcohol, 5 mg/mL TPGS and 3  mg/mL PEG 6000 MS yielded the greatest entrapment efficiency and drug loading among 20 formulations. The F(10) and F(15) formulations contained KP extract concentrations of 0.96 and 1.44  mg/mL, respectively, with entrapment efficiency as high as 87%. The permeated amount of KP through skin from SLNs was significantly higher compared that from gel formulation (Sutthanut et al. 2009) (Table 3). TPGS has been reported to provided favorable partitioning of drugs into skin and to enhance drug flux by decreasing the interfacial tension and interfacial barrier function of SC.

Gel and nanogel Griseofulvin (a BCS class II drug with antifungal property) is slowly, erratically, and incompletely absorbed from the gastrointestinal tract in humans. The clinical failure of the oral therapy of griseofulvin mainly comes from its poor solubility and appreciable inter- and intra-subject variation in bioavailability from different commercial products (Aggarwal et al. 2012). Aggarwal et al. formulated a topical formulation of griseofulvin, which would deliver the drug locally with a therapeutically effective concentration. Griseofulvin was completely solubilized in ethanol, TPGS, and mixture of ethanol with varying amounts of TPGS. Finally, it was incorporated in the carbopol 980 NF base (Table 4). The formulations were characterized and evaluated ex vivo using Laca mice skin, microbiologically against Microsporum gypseum and Microsporum canis, histopathologically in mouse and clinically in a small group of patients. The study revealed that TPGS and ethanol individually and synergistically improved the drug permeation as well as drug retention in the skin (Table 4). Interestingly, the more TPGS formulation had, the higher griseofulvin retained

Application of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in transdermal… Table 3 Permeation of flavonoids from F(15) and KP gel formulations through EPI-212X EpiDerm™ skin samples (Sutthanut et al. 2009)

Total flavonoids

Quantity of flavonoids (µg)

F(15) SLN formulation (n = 3)

KP gel formulation (n = 3)

Initial amount at t = 0 In donor compartment Retained in skin Retained per mg skin In receiver compartment % Mass balance

537.99 365.63 ± 26.10 5.10 ± 1.11 0.55 ± 0.13 95.57 ± 9.08* 81.24 ± 3.11

651.91 446.05 ± 18.75 4.16 ± 0.29 0.55 ± 0.05 81.04 ± 5.82* 81.49 ± 3.49

Flavonoid

F(15) SLN formulation (n = 6)

Selected 3,5,7,3′,4′-pentamethoxyflavone flavonoids 5,7-dimethoxyflavone 3,5,7,4′-tetramethoxyflavone 5,7,4′-trimethoxyflavone

KP gel formulation (n = 6) 2

Percent permeated

Flux (Js) [µg/(cm /h)]

Percent permeated

Flux (Js) [µg/(cm2/h)]

21.78 ± 6.48

1.67 ± 6.48#

14.91 ± 4.21

1.40 ± 0.05#

26.57 ± 3.26 29.54 ± 7.32 21.37 ± 4.58

0.80 ± 0.09 7.49 ± 0.50# 3.48 ± 0.07#

17.91 ± 0.78 20.86 ± 3.69 15.40 ± 0.84

0.73 ± 0.03 6.39 ± 0.54# 2.97 ± 0.19#

F(15) is the SLNs formulation containing KP extract 1.28 mg/mL KP gel is the gel formulation containing KP extract 1.44 mg/mL *Significant difference (p < 0.05) of total skin permeated amounts of KP flavonoids in F(15) and KP gel formulation #

Significant difference (p < 0.05) of flux of flavonoids in F(15) and KP gel according to same flavonoids

Table 4 Composition and TDDS parameters of various Griseofulvin formulations (Aggarwal et al. 2012) Quantity (g), formulation codes Ingredients

FI

F II

F III

F IV

FV

F VI

F VII

F VIII

Griseofulvin Ethanol TPGS PG Carbopol 980 NF Triethanolamine Triple distilled water (q.s.)

0.02 – – – 0.1 0.2 10.0

0.02 – 0.5 0.5 0.1 0.2 10.0

0.02 4.0 – 0.5 0.1 0.2 10.0

0.02 4.0 0.1 0.5 0.1 0.2 10.0

0.02 4.0 0.2 0.5 0.1 0.2 10.0

0.02 4.0 0.3 0.5 0.1 0.2 10.0

0.02 4.0 0.4 0.5 0.1 0.2 10.0

0.02 4.0 0.5 0.5 0.1 0.2 10.0

Amount of griseofulvin (µg/cm2), formulation codes TDDS parameters

FI

F II

F III

F IV

FV

Cumulative amount permeated of griseofulvin in 24 h Skin retention of griseofulvin in 24h Enhancement ratio of permeation amount Enhancement ratio of skin retention

10.28 ± 1.25 47.35 ± 1.43 62.69 ± 1.25 76.58 ± 1.64 84.52 ± 0.90

F VI

F VIII

94.35 ± 0.46 108.65 ± 0.96 111.98 ± 1.36

0.65 ± 0.15

15.49 ± 0.49 12.23 ± 0.51 22.88 ± 1.11 F IV < F V < F VI < F VII < FVIII

1.00

4.61

6.06

7.45

8.22

1.00

23.83

18.82

35.20

F IV < F V < F VI < F VII < FVIII

inside skin. However, when ethanol replaced TPGS in F3, cumulative permeated amount of griseofulvin for F3 was significantly higher than that for F2 (only TPGS) (Table 4).

F VII

9.18

36.77 ± 1.13

10.57

10.89

56.57

Therefore, ethanol maybe facilitated permeation of griseofulvin through mice skin more than TPGS. In general, the topical formulation of griseofulvin potentially was an

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C. V. Pham, C.-W. Cho

effective and convenient alternative to the currently available oral therapy for the treatment of superficial fungal infections (Aggarwal et al. 2012). Similarly, Mohammed revealed good improvement of skin permeation characteristics of diclofenac sodium using sodium carboxymethylcellulose gels containing permeation enhancers such as TPGS and Tween 80 as compared to the commercial gels including Voltaren® Emulgel® (Ciba-Geigy, Switzerland, lot B 34 6600); Inflaban® gel (Co-L.t.d. Sult-Jordan, lot 329); Diclogesic® gel (Dar AlDawa, Jordan, lot 2159); Diclofen® gel (United Pharm. Co., Jordan, lot 80605). Skin permeation enhancers such as Tween 80, TPGS, and isopropyl alcohol (IPA) expressed little or no effect on the permeation characteristics of diclofenac sodium. According to the cumulative permeated amount of diclofenac sodium, the tested formulations could be arranged in the following descending order: 0.5% Tween 80 > combination II > control gel > 5% IPA > 5% TPGS > Voltaren® Emulgel® > Inflaban® > Diclogesic® > Diclofen® gel (Mohammed 2001). Amphotericin B was marketed for effective treatment of cutaneous fungal infections (0.1% w/w Life Care Innovations Pvt. Ltd., Gurgaon, India). It was reported that the optimized nanogel exhibited the enhancement ratio of amount of drug deposited and transdermal flux was found to be 3.2 and 3.9, respectively compared to marketed product. This significant enhancement is due to the synergistic effect by the use of nanoemulsion as a carrier and TPGS as a permeation enhancer (Kaur et al. 2015).

Micro- and nano-emulsions Several types of nanocarriers have been effectively used to dissolve and deliver lipophilic drugs through viable skin. Micro-emulsions (ME) are a very interesting system due to their thermodynamic stability, ease of preparation, and skin penetration-enhancing ability (Carvalho et al. 2016; Lopes 2014; Santos et al. 2008; Kogan and Garti 2006). In detail, ME may increase topical or transdermal delivery of a compound by different mechanisms. First, a large amount of drug can be loaded in ME due to their high solubilization power. Second, penetration enhancement can be expected because the thermodynamic activity of the drug in the system can be modified to favor partitioning into SC. Third, the surfactants in ME systems may reduce the diffusional barrier of SC (Suppasansatorn et al. 2007). The ME were developed with polyoxyethylene ten oleoyl ether, TPGS, and ethanol (2.8:1:0.2, w/w/w) as surfactantco-surfactant blend and tributyrin, isopropyl myristate (IPM), and oleic acid (OA) as oil phase. As polar phase, propylene glycol or water was used (26% w/w) (Carvalho et  al. 2016). The penetration of all lipophilic compounds

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into the SC was significantly enhanced by 2.3- to 3.8-fold in contrast to the control solutions. For delivery into viable skin layers, penetrated amount of progesterone and tocopherol was increased by 2.5- and 26-fold (p < 0.05), respectively, while penetration of lycopene improved approximately 38-fold (Carvalho et al. 2016). ME were chosen as a potential vehicle for temozolomide acid hexyl ester (TMZA-HE) topical formulations (Suppasansatorn et  al. 2007). ME systems were constructed with either OA or IPM as the oil phase and TPGS as a surfactant. The data showed that TMZA-HE fluxes from ME formulations were sevenfold higher than those from their neat oil constituents (Suppasansatorn et al. 2007). Meanwhile, lipid-based nano-emulsions (NEs) can be particularly effective to the topically applied drugs thanks to potential advantages such as hydration of the epidermis, and the sustained release, thus avoiding the buildup of toxic drug concentrations in the skin (Brownlow et  al. 2015; Pham et al. 2014; Paudel et al. 2010; de Leeuw et al. 2009; Kogan and Garti 2006). NEs also are thermodynamically stable systems of oil and water, stabilized by an interfacial film of surfactant and co-surfactant (Brownlow et al. 2015; Date et al. 2010). NEs can be employed to effectually enhance the solubility of both lipophilic and hydrophilic compounds (Brownlow et al. 2015; Date et al. 2010). Additionally, NEs have been shown to improve the bioavailability and efficacy of diversity of natural compounds, such as camptothecin analogues, taxanes, vinca alkaloid, and flavonoids (Brownlow et al. 2015; Pham et al. 2013; Han et al. 2009). Brownlow and co-workers developed optimal GenisteinTocomin® NE (Gen-Tocomin® NE) for dermal photoprotection (Brownlow et  al. 2015). Physicochemical characterization and photostability studies show NE formulations utilizing surfactant mixture (Smix) of Solutol® HS-15 (SHS15) blended with TPGS as co-surfactant (Fig. 6) was significantly superior to formulations that employed poloxamer 188. Gen-Tocomin® NE also expressed excellent biocompatibility, and provided considerable UVB protection to cultured subcutaneous L929 fibroblasts.

Other applications The effect of micellar solubilization on solubility enhancement and permeation enhancement of estradiol by TPGS was characterized (Sheu et  al. 2003). Results showed that the solubility of estradiol was improved in the presence of TPGS according to concentration-dependent manner through micellar solubilization. By analyzing fourier transformation infrared spectrometry and differential scanning calorimetry, Liou and co-workers dedicated that there were no the biophysical changes in lipids and

Application of D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in transdermal… Fig. 6 Schematic diagram of preparation of Tocomin® NE incorporating genistein, showing components of oil phase components (Tocomin® R 50%: vitamin E tocotrienols and tocopherols; IPM), surfactant mixture (SHS15, TPGS, or poloxamer 188), along with ethanol co-solvent loading of genistein (Gen) and emulsification process steps. Representative graphs of particle size distribution (a) and ζ-potential (b) are also shown (Brownlow et al. 2015)

protein structures in the SC when TPGS/EtOH added in the formulation (Liou et al. 2009). Entrapment of poorly soluble drugs in micelles of surfactants may reduce the drug’s thermodynamic activity as well as the free-form concentration of drug. Also, it reduced the equilibrium distribution constant, subsequently impaired its passive diffusion (Guo et al. 2013; Sheu et al. 2003). Other studies have confirmed that the permeability of drug was also found to be reduced in a concentration-dependent manner in the presence of poloxamer 188 (Guo et  al. 2013; Fischer et al. 2011). In another study, TPGS was employed in water/ethanol/ PEG 400 solutions to deposit minoxidil in SC (Sheu et al. 2006); in liquid crystalline systems containing nicotine for the controlled transdermal delivery (Borgheti-Cardoso et  al. 2016); in nanoemulsion containing aceclofenac and capsaicin to induce 2.02 and 1.97-fold more permeation of aceclofenac and capsaicin, respectively through dermatomed human (Somagoni et  al. 2014); in unique dispersion systems containing progesterone prepared by supercritical fluid processing (Falconer et al. 2014).

Conclusions TPGS can be combined with other enhancing technique to formulate novel formulations with higher effective, precise, and safe drug delivery drug through skin or inside in skin. Acknowledgements National University.

This study was supported by Chungnam

Compliance with ethical standards Conflict of interest All authors declare that they have no conflict of interest.

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