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Preparation and Characterization of Stable pH-Sensitive Vesicles Composed of α-Tocopherol Hemisuccinate

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Abstract

The current study aims to develop a stable pH-sensitive drug delivery system. First, cleavable polyethylene glycol-α-tocopherol hemisuccinate (PEG-THS) was synthesized. Conventional pH-sensitive vesicles composed of the Tris salt of α-tocopherol hemisuccinate (THST) were then prepared using the detergent removal technique. The vesicles had a mean particle size of (163.8 ± 5.5) nm and a zeta potential of −74.5 ± 6.4 mV. The THST vesicles were then modified using PEG-THS or uncleavable PEG-cholesterol (PEG-CHOL) (THST/PEG-lipids, 100:6 molar ratio). The mean vesicle particle size and absolute zeta potential decreased with increasing PEG-THS proportion. When the pH was decreased, the vesicle particle size and calcein release rate increased. The THST vesicles were initially Ca2+-unstable but exhibited significantly improved stability after modification with PEG-THS, especially at PEG-lipid ratios above 6%. Incubation in an acid serum increased the calcein release rate of conventional THST vesicles to 45 ± 1.98% at 10 min. However, the release rate of the PEG-CHOL vesicles remained low. The calcein release rate of PEG-THS vesicles was between those of conventional and PEG-CHOL-V. Therefore, PEG-THS can protect vesicles in serum and reconstitute their pH sensitivity in acidic conditions. Cleavable PEG-THS can be used in stable pH-sensitive preparations without loss of pH sensitivity. Free calcein and conventional vesicles eliminated from the plasma soon after injection, as well as the half-life (t 1/2) and area under the curve of PEG-THS-V encapsulating calcein, were dramatically increased. This phenomenon indicates that the use of PEG-lipid derivatives has gained a favorably long circulation effect in mice.

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Abbreviations

Calcein-S:

Calcein solution

THST Vesicles:

Tris (hydroxymethyl) aminomethane salt of alpha-tocopherol hemisuccinate vesicles

Calcein-TV:

Calcein-tris (hydroxymethyl) aminomethane salt of alpha-tocopherol hemisuccinate vesicles

PEG-THS:

Poly(ethylene glycol)-alpha-tocopherol hemisuccinate

PEG-CHOL:

Poly(ethylene glycol)-cholesterol

PEG-THS-V:

Poly(ethylene glycol)-alpha-tocopherol hemisuccinate vesicles

PEG-CHOL-V:

Poly(ethylene glycol)-cholesterol vesicles

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Acknowledgement

This work was supported by National Natural Science Foundation of China (81072602 and 81102394).

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Authors and Affiliations

  1. College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, People’s Republic of China

    Huan Xu & Kai-Qian Wang

  2. School of Pharmacy, Shenyang Pharmaceutical University, Mailbox 42, Wenhua Road 103, Shenyang, 110016, People’s Republic of China

    Yi-Hui Deng & Da-Wei Chen

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  1. Huan Xu
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  2. Yi-Hui Deng
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  3. Kai-Qian Wang
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  4. Da-Wei Chen
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Correspondence to Huan Xu or Yi-Hui Deng.

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Xu, H., Deng, YH., Wang, KQ. et al. Preparation and Characterization of Stable pH-Sensitive Vesicles Composed of α-Tocopherol Hemisuccinate. AAPS PharmSciTech 13, 1377–1385 (2012). https://doi.org/10.1208/s12249-012-9863-7

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