A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson’s disease

Abstract

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson’s disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics

“…Deep Eutectic Solvent Synthesis and Formulation Preparation: Deep eutectic solvents were synthesized as previously described. [30,37] Briefly, weak acids of desired anions were dissolved in minimal ultrapure water in a round bottom flask. The solution was heated, with stirring, using an oil bath to 40 °C in the case of the choline-based DESs and 65 °C in the case of the acetylcholine-based DESs.…”

“…The structure was then confirmed using nuclear magnetic resonance (Bruker AVANCE NEO 400). [31,37] To prepare insulin formulations, lyophilized insulin was suspended in saline. Sufficient DES was added and in cases where this addition did not dissolve insulin, 1 m hydrochloric acid was added to adjust the pH to 2.5-3 and the solution became clear.…”

“…[30] These DESs were designed to exhibit a range of chemical properties, especially hydrophobicity as this parameter is expected to be a key determinant of their ability to impact transport and subsequent absorption in the subcutaneous tissue. Choline and acetylcholine were investigated as the two cations because choline has been a commonly explored cation in previous studies of ionic liquids [30][31][32][33][34][35][36][37] and acetylcholine is structurally similar but a more hydrophobic cation. These cations were subsequently paired with five anions, glycolate, lactate, propionate, hexenoate, and geranate, that covered a spectrum of molecular weights, carbon chain lengths, and hydrophobicities (Table S1, Supporting Information).…”

An overview of biomedical applications of choline geranate (CAGE): a major breakthrough in drug delivery

“…ILs and DESs are have recently been proposed as biocompatible solvents for facile drug delivery and CAGE is one of them. It has proven to be an efficient drug delivery model for transdermal, 40 buccal, and subcutaneous delivery of intractable drugs with the least toxicity 41,42 efficient skin permeation, 43 less irritation, and the ability to achieve target therapeutic goals with minimum side effects. Fig.…”

“…Thus, DES maintains its drug concentration in plasma by substituting three injections per day with three injections per week. 41 …”