9. A novel dextran hydrogel linking trans-ferulic acid for the stabilization and transdermal delivery of vitamin E

Abstract

Long-term exposure of the skin to UV light causes degenerative effects, which can be minimized by using antioxidant formulations. The major challenge in this regard is that a significant amount of antioxidant should reach at the site for effective photoprotection. However, barrier properties of the skin limit their use. In the present study, vitamin E (α-tocopherol) was loaded into a dextran hydrogel containing ferulic moieties, covalently linked, to improve its topical delivery, and also to increase its relative poor stability, which is due to direct exposure to UV light. Methacrylic groups were first introduced onto the dextran polymer backbones, then the obtained methacrylated dextran was copolymerized with aminoethyl methacrylate, and subsequently esterificated with trans-ferulic acid. The new biopolymer was characterized by Fourier transform infrared spectroscopy. The values of content of phenolic groups were determined. Its ability in inhibiting lipid peroxidation in rat liver microsomal membranes induced in vitro by a source of free radicals, that is tert-butyl hydroperoxide, was studied. Hydrogel was also characterized for swelling behaviour, vitamin E loading efficiency, release, and deposition on the rabbit skin. Additionally, vitamin E deposition was compared through hydrogels, respectively, containing and not containing trans-ferulic acid. The results showed that ferulate hydrogel was a more effective carrier in protecting vitamin E from photodegradation than hydrogel without antioxidant moieties. Then antioxidant hydrogel could be of potential use for cosmetic and pharmaceutical purposes as carrier of vitamin E that is an antioxidant that reduces erythema, photoaging, photocarcinogenesis, edema, and skin hypersensitivity associated with exposure to ultraviolet B (UVB) radiation, because of its protective effects.

Tocopherols, Tocotrienols and Their Natural Sources

Vitamin E comprises of three homologous series: tocopherols, tocotrienols and tocomonoenols.  Both tocopherols and tocotrienols have four homologues each: α-, β-, γ- and δ-tocopherols, and α-, β-, γ-and δ-tocotrienols respectively whereas there are only two isomers for α-tocomonoenol and a δ-tocomonoenol reported.  α-Tocopherol has the highest bioavailability in the plasma irrespective of the vitamin E contents in food intake, consequently α-tocopherol was considered as the only significant vitamin E and other members of the vitamin E family was often ignored.

 Fig. 1: Structures of tocopherols and tocotrienols

The molecular structures of tocopherols and tocotrienols are very similar, sharing the same chroman ring (as indicated by the purple circle in Figure 1).  The difference between the two is that tocopherol has saturated side chain whereas the remaining acylic side chain of tocotrienol comprises three isoprene units, therefore has three double bonds at the side chain.  The difference has the following implications: a C–C single bond (154 pm) is longer than a C=C double bond (133 pm). Saturated phytyl side chain has regular tetrahedral structure whereas the regular structure in geranylgeranyl side chain is disrupted by the plane trigonal structure at the double bonds. The bond angles at the olefinic carbons are larger (about 120º) as compared to that at the saturated carbons (about 109.5º). Double bonds are more rigid than single bonds as the additional π bond restrict the free rotation of σ bond. The 3-dimensional conformation of side chain (depends on bond lengths and bond angles), the electron density and rigidity shall affect the binding affinities of tocotrienols with the α-tocopherol transfer protein (with specific ligand-binding sites) [1, 2] and hence their bioavailability in humans. Figure 1 also reveals that tocopherols have three chiral centers and hence have eight stereoisomers each whereas tocotrienols have only one chiral center and hence have only two stereoisomers. Natural Sources of Tocotrienols Table 1.  Composition of Tocopherols and Tocotrienols from Selected Sources Source α-T β-T γ-T δ-T Total T α-T3 β-T3 γ-T3 δ-T3 Total T3 50mg T3 Palm oil 182 182 170 25 301 122 618 81g Rice bran oil 129 6 23 3 161 57 8 78 2 145 345g Oat 14.9 3.0 0.4 18.3 56.4 5.4 61.8 809g Barley 8.6 0.9 5.6 0.7 15.8 40.3 8.7 10.4 0.9 60.3 829g Soft wheat 15.9 9.5 25.4 6.4 42.5 48.9 1022g Durum wheat 8.4 4.8 13.2 6.9 39.6 46.5 1075g Spelt 10.3 7.0 17.3 5.5 32.7 38.2 1309g Triticale 13.6 6.5 20.1 6.2 32.0 38.2 1309g Rye 14.4 3.5 0.5 18.4 16.9 13.0 0.3 0.2 30.4 1645g Maize 3.7 0.2 45.0 1.0 49.9 5.3 11.3 0.4 17.0 2941g Data for cereals:  Panfili et al. 2003 [3]; Ryynänen et al. 2004 [4].   In contrast to ubiquitous tocopherols, natural sources of tocotrienols are very scarce.  Cereals contain small quantities of tocotrienols but polished rice does not contain tocotrienols after removal of the rice bran.  Other than palm oil and rice bran oil, vegetable oils such as soybean, rapeseed and sunflower oils, practically do not contain tocotrienols.  The ratio of tocopherols to tocotrienols in palm oil is about 23:77 whereas that for rice bran oil varies widely from 23:52 to 43:46. Table 1 indicates that in order to have 50 mg equivalent of tocotrienols, one has to consume about 81 g of crude palm oil, 345 g of rice bran oil or ranging from one to three kg of cereals/grains per day.  A recent study indicates that fruits and vegetables contain very little tocotrienols [5] and even larger daily consumption is needed in order to achieve 50 mg equivalent of tocotrienols. Even at that large quantity of food intake, the bioavailability of tocotrienols is expected to be depressed significantly by the presence of tocopherols. Tocotrienols are essential for chemoprevention of degenerative diseases.  Currently perceived “balance diet” is unachievable, in terms of tocotrienols. Global annual production of palm oil exceeds 40 million tons whereas that for rice bran oil is only 3 million tons, out of which 2 million tons are unsuitable for human consumption.  Therefore palm oil is the best and most reliable natural source for tocotrienols.  Although palm oil is the best natural source for tocotrienol, it contains too high α-tocopherol, causing the tocotrienol-rich fraction extracted from palm oil to be far from ideal.  However, appropriate processing technology can reduce the α-tocopherol content in tocotrienol-rich fraction. References [1]    Meier R, Tomizaki T, Schulze-Briese C, Baumann U and Stocker A (2003).  The molecular basis of vitamin E retention: Structure of human α-tocopherol transfer protein.  J Mol Biol 331(3): 725-734. [2]    Min C K, Kovali R A and Hendrickson W A (2003).  Crystal structure of human α-tocopherol transfer protein bound to its ligand: Implications for ataxia with vitamin E deficiency.  PNAS100(25): 14713-14718. [3]    Panfili G, Fratianni A and Irano M (2003).  Normal phase high-performance liquid chromatography method for the determination of tocopherols and tocotrienols in cereals.  J Agric Food Chem 51(14): 3940-3944. [4]    Ryynänen M, Lampi A-M, Salo-Väänänen P, Ollilainen V and Piironen (2004).  A small-scale sample preparation method with HPLC analysis for determination of tocopherols and tocotrienols in cereals.  J Food Composition and Analysis 17(6): 749-765. [5]    Chun J, Lee J, Ye L, Exler J and Eitenmiller R R (2006).  Tocopherol and tocotrienol contents of raw and processed fruits and vegetables in the United States diet.  J Food Composition and Analysis 19(2-3): 196-204.

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