Thermoresponsive engineered emulsions stabilised with branched copolymer surfactants for nasal drug delivery of molecular therapeutics

Abstract

Novel branched copolymer surfactants (BCS) allow the formation of oil-in-water emulsions that exhibit a temperature-induced liquid-to-gel transition. If the temperature of this transition is between room and body temperature (ca 25 and 37 °C, respectively), then the emulsions form a gel in situ upon contact with the body. A major advantage of this in situ gelation is the potential to manipulate the materials at room temperature in the low viscosity liquid state, then administer them to the body to initiate a switch to a retentive gel state, which could be used to deliver drugs to challenging sites such as the nasal mucosa.

There are, however, several important factors which have not been explored for thermoresponsive BCS-stabilised emulsions to progress their use towards this application. Neither the delivery of drugs from the materials, the retention on tissue, nor the impact of co-formulated drugs on the thermoresponsive behaviours, are known. Furthermore, it has not been demonstrated that the materials are compatible with devices to generate sprays of the correct profiles for nasal administration. In this study we investigate the potential of thermoresponsive BCS-stabilised emulsions for the nasal delivery of licensed molecular therapeutics to examine the potential of BCS emulsion systems as a carrier for medicines.

It was found that thermoresponsive behaviours can be maintained in the presence of drug substances, and that the liberation of the incorporated drugs occurs in a sustained manner. The BCS appear to have comparable cytotoxicity to common excipients and significantly enhanced retention on nasal tissue compared to even well-established mucoadhesives. The emulsions were incorporated into a spray device to demonstrate that the materials can be atomised with a plume appropriate for nasal administration prior to in situ gelation.

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Materials

Di(ethylene glycol) methyl ether methacrylate (DEGMA, 95 %), poly(ethylene glycol) methyl ether methacrylate (PEGMA, Mn 950 gmol−1), ethylene glycol dimethacrylate (EGDMA, 98 %), 1-dodecanethiol (DDT, 99 %), anhydrous dodecane (99 %), absolute ethanol, acetonitrile (gradient grade) and methyl cellulose (2000 cP, 2 % aqueous solution at 20 °C) were purchased from Sigma-Aldrich (UK). α,α-azobisisobutyronitrile (AIBN, >99 %) was obtained from Molekula (UK). Sodium dihydrogen phosphate dihydrate (99 %), orthophosphoric acid (85 %), potassium dihydrogen phosphate (99 %) and 1-octanesulphonic acid sodium salt (98 %) were supplied by VWR (UK). Dialysis tubing with molecular weight cut off (MWCO) of 14 kDa was purchased from Sigma Aldrich (UK). Chitosan (50–190 kDa; deacetylation degree 20.8 ± 0.5 %), dextran (average molecular weight 4000 Da), phenylephrine hydrochloride and lidocaine hydrochloride were purchased from Sigma Aldrich (UK). Micronised budesonide was supplied by LMG Pharma (Boca Raton, USA). Phosphate buffered saline (PBS) tablets were purchased from Oxoid (UK). Tween 20 was purchased from Fluka Analytical, UK. Potassium dihydrogen orthophosphate, octane sulphonic acid sodium salt, orthophosphoric acid, sodium dihydrogen phosphate dihydrate, absolute ethanol, and gradient grade acetonitrile were purchased from VWR (UK). Deionised water was employed in all experiments and produced in-house by reverse osmosis. All chemicals were used as received. Mechanical nasal spray pumps delivering 100 μL of formulation per actuation were provided by Bespak. The optimal BCS system was synthesised and described in our previous studies (denoted as BSC5).

Abhishek Rajbanshi, Eleanor Hilton, Emily Atkinson, James B. Phillips, Shiva Vanukuru, Vitaliy V. Khutoryanskiy, Adam Gibbons, Sabrina Falloon, Cecile A. Dreiss, Darragh Murnane, Michael T. Cook, Thermoresponsive engineered emulsions stabilised with branched copolymer surfactants for nasal drug delivery of molecular therapeutics, International Journal of Pharmaceutics, Volume 676, 2025, 125506, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125506.

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