Elsevier

Journal of Molecular Liquids

Volume 324, 15 February 2021, 114930
Journal of Molecular Liquids

Poloxamine/D-α-Tocopheryl polyethylene glycol succinate (TPGS) mixed micelles and gels: Morphology, loading capacity and skin drug permeability

https://doi.org/10.1016/j.molliq.2020.114930Get rights and content

Highlights

  • NA is extensively included into the hydrophobic core of TPGS-poloxamine mixed micelles.

  • Micelle core expands because of the preferential accumulation of the drug in that compartment.

  • Naproxen load in the micelles increases markedly with the temperature.

  • Micellar thermogels of TPGS-poloxamine maintain their 3D structure upon drug loading.

  • Diffusion of NA from the thermogels increases by incorporating TPGS into the micelles.

Abstract

The combination of polymeric surfactants with different features into mixed micelles give access to properties that may be superior to the single-component micelles. In this work, we investigated synergistic effects in mixtures of D-α-Tocopheryl polyethylene glycol succinate (TPGS) with poloxamines (also known as Tetronic), pH-responsive and thermogelling polyethylene oxide (PEO)-polypropylene oxide (PPO) 4-arm block copolymers. We examined the morphology of the self-assembled micelles of TPGS with Tetronic 1107 (T1107) and 908 (T908) in the presence of naproxen (NA), used as a model drug, and assessed the capacity of the single and mixed micelles to trap the guest, using a combination of small-angle neutron scattering (SANS) and NMR spectroscopy (1D, 2D-NOESY and diffusion NMR), over a range of compositions and temperatures, in the dilute regime and gel state. NA did not interact with T1107 or T908 in their unimer form, but it was incorporated into the hydrophobic core of the micelles above the critical micellar temperature (CMT). In contrast, TPGS dissolved NA at any temperature, mainly in the tocopherol core, with some partitioning in the PEG-shell. The micellar structure was not altered by the presence of NA, except for an expansion of the core size, a result of the preferential accumulation of NA in that compartment. The solubility of the drug in single component micelles increased markedly with temperature, while mixed micelles produced an intermediate enhancement of the solubility between that of TPGS and the poloxamines, which increased at higher TPGS/poloxamine ratios. Micellar hydrogels formed by the packing of the polymeric mixed micelles in a BCC macrolattice, whose structure was not altered by the presence of the drug (at least at 0.2 wt%). The applicability of the drug-loaded gels for topical formulations was explored by transdermal diffusion testing using a synthetic model of skin, showing that the diffusion of NA across the membrane was enhanced by incorporating small amounts of TPGS to the hydrogel, especially with the more hydrophilic T908.

Introduction

Amphiphilic block copolymers spontaneously-self-assemble into nanosized colloidal structures with narrow size distributions [1], and constitute the simplest type of polymer-based nanocarriers. Specifically, polymeric micelles form above the critical micellar concentration (CMC) and critical micelle temperature (CMT) [2], where the micelle core, formed by the hydrophobic segments of the copolymer, provides the entrapment locus for hydrophobic molecules and controls their release profile, while the hydrophilic shell stabilizes the core and ensures the solubilisation stability of the aggregate [[3], [4], [5], [6], [7]]. Raising the concentration and/or temperature can lead to further organization of the polymeric micelles into physical gels, which provides opportunities for sustained delivery from a depot and other biomedical applications [[8], [9], [10]]. A wide variety of copolymers can be used to produce polymeric micelles and hydrogels, whose physicochemical and biological properties can be tuned by changing the configuration, architecture or ratio of the constituting blocks [10].

Among the amphiphilic block copolymers based on polyethylene oxide (PEO) and polypropylene oxide (PPO), the family of Tetronic® (BASF) surfactants (also known by the generic name of poloxamines), is attracting increasing attention [[11], [12], [13]]. They present a four-arm star structure, in which a central ethylene diamine spacer connects the arms, each formed by a PPO and a PEO block. They are characterized by pH- responsiveness, due to the protonation of the central diamine group [14,15], as well as a rich phase behaviour, modulated by varying the length of the blocks. Different molecular weights, hydrophilic-lipophilic balance (HLB), CMC and CMT, or gel point can thus be obtained [16,17]. Response to temperature and pH changes make Tetronic micelles and gels interesting, specifically as nanocarriers for controlled drug and protein release [[18], [19], [20], [21]], thus expanding the range of applications of their linear counterparts, Pluronic® [[22], [23], [24]].

D-α-Tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble derivative of vitamin E with a polyethylene glycol (PEG) chain which is attracting great interest [25,26]. TPGS shares with poloxamines the ability to form polymeric micelles and the type of hydrophilic part, while inhibiting more efficiently the activity of P-glycoprotein transporters (P-gp), responsible for the poor permeability of many anticancer drugs through physiological barriers [27,28]. TPGS-1000, which comprises a 23 ethylene oxide (EO)-unit hydrophilic block, has been the most studied to date. It self-aggregates at 0.02%, forming spherical core-shell micelles of aggregation number around 100, which are very stable with temperature [29].

Considering the interesting features of both Tetronic and TPGS, it is expected that their mixtures may combine pH- and temperature responsiveness and gelation capacity (Tetronic), with the higher biocompatibility and potential antioxidant properties of TPGS, expanding the range of drugs that can be loaded, their release profiles, and modifying their permeability across barriers [30]. There are very few studies in the literature on the combinations of different Tetronic for the solubilisation of drugs [31,32], as well as on the combined use of TPGS and poloxamines [33,34]. Recently, we have reported a detailed structural characterisation by scattering and spectroscopic methods of TPGS-Tetronic mixtures, using Tetronic 1107 (60 EO and 20 PO units per arm), and Tetronic 908 (114 EO and 21 EO units per arm) [35]. Spherical core-shell micelles comprising both surfactants in their structure (mixed micelles) were found to form, in which Tetronic unimers incorporate into TPGS aggregates below the CMT of the poloxamine, while mixed micelles only form under limited conditions with T908. At high concentration and body temperature, small proportions of TPGS extend the gel phase and significantly improve the cell viability of NIH/3 T3 fibroblasts, making poloxamine gels doped with TPGS promising platforms for drug delivery as ointments, to promote the topical administration of drugs.

In this work, we investigate the capacity of the mixed micelles and gels formed from TPGS, Tetronic 1107 and Tetronic 908 to encapsulate the anti-inflammatory naproxen. This molecule was selected because of its well-established quantification methods [[36], [37], [38]] and its hydrophobic character, which makes it a suitable model to test the solubility and permeability of poorly water-soluble drugs. Specifically, we examined the morphology of the self-assembled structures of TPGS, Tetronic and their mixtures in the presence of the drug over a range of compositions and temperatures, using a combination of small-angle neutron scattering (SANS), NMR methods (1D, 2D-NOESY and diffusion NMR). The solubilisation capacity of the micelles was quantified by diffusion NMR and fluorescence spectroscopies, and the applicability of the gels for topical formulations explored by transdermal diffusion testing using a synthetic model of skin (Strat-M® membranes).

Section snippets

Materials

Tetronic® 1107 (T1107) and Tetronic® 908 (T908) were a gift from BASF (Ludwigshafen, Germany). The reported composition per arm is 60 ethylene oxide (EO) and 20 propylene oxide PO for T1107, with an average molecular weight 15,000 g·mol−1. T908 comprises 114 EO and 21 PO, with an average molecular weight of 25,000 g·mol−1. D-α-Tocopheryl polyethylene glycol succinate (TPGS), with PEG molecular weight of 1000 (23 EO), and naproxen (NA, purity ≥98.5%) were obtained from Sigma-Aldrich (Merck

Solubilisation of NA in T1107 and TPGS micelles

Tetronic 1107 self-aggregates into core-shell micelles above 35 °C, at 1% concentration [40]. The interactions between a saturated solution of NA and 1% T1107 was studied first by 1H NMR at 25 °C, below the CMT of the poloxamine. No changes in the resonances of the aromatic protons of NA (7–8 ppm, SI, Fig. S1) are detected (Fig. 1A), suggesting a lack of interaction between the drug and the poloxamine in unimer form. To further confirm this, NMR diffusion experiments were performed on

Conclusions

Mixtures of TPGS, a water-soluble derivative of vitamin E, with two Tetronic surfactants (T1107 and T908) were investigated in the sol and gel state in the presence of naproxen (NA). Both types of surfactants are PEO-based copolymers capable of forming mixed micelles that combine the biocompatibility and antioxidant properties of TPGS with the pH- and temperature responsiveness, and gelation capacity of the poloxamines.

Regarding the dilute regime, NA does not interact with T1107 or T908 in

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors thank JCNS for the provision of beam time to the KWS-2 diffractometer at the Heinz Maier-Leibnitz Zentrum (MLZ, Garching, Germany) and to Prof. G. Tardajos and Prof. A. Guerrero (UCM), for their help with the NMR measurements. H. Lana (UN) is acknowledged for his assistance with the permeability studies. The authors also thank undergraduate students J. Burriel and J. Carriles for their help with the diffusion NMR experiments. Financial support from project SAF2017-83734-R of the

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