Aripiprazole, marketed under the brand name Abilify®, belongs to the class of atypical antipsychotics. It functions as a partial agonist at both D2 dopamine receptors and serotonin 5-HT1A receptors [1]. Since 2002, it has been used orally to treat schizophrenia and bipolar disorder at doses of 10–30 mg/day [2]. Common side effects of this medication include sedation, weight gain, and the occurrence of extrapyramidal symptoms. In 2013, the Abilify Maintena® brand entered the American pharmaceutical market as a monthly extended-release injectable suspension of aripiprazole monohydrate. The vial contains two coupling syringes, with the first syringe containing 300 or 400 mg of medicinal powder with sodium carboxymethyl cellulose (16.64 and 12.48 mg), mannitol (62.4 and 83.2 mg), sodium phosphate monobasic monohydrate (1.11 and 1.48 mg), and sodium hydroxide, and the second syringe containing WFI water (1.9 and 1.5 ml). Before injection, the syringes are paired with each other, and with 30 s of round-trip movement of the syringes, a suspension ready for intramuscular (IM) injection is prepared [3]. After the first Abilify Maintena® injection, treatment should continue with oral aripiprazole (10–20 mg) or another oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy [3].

Slow-release formulations of aripiprazole as an IM suspension can produce an initial burst release at the beginning of the injection [4]. To address this issue, a slow subcutaneous (SC) release formulation based on lipid liquid crystal (LLC) has been developed [5]. Buvidal®, the monthly slow-release LLC formulation of buprenorphine, was introduced to the European pharmaceutical market in 2018 and has been able to maintain a stable concentration over a month. The LLC of buprenorphine consists of phosphatidylcholine (PC), glycerol di-oleate (GDO), and N-methyl-2-pyrrolidone (NMP) solvent. As soon as this formulation is injected subcutaneously, it turns into a gel by absorbing water, creating a drug matrix (depot) that slowly releases the drug over the course of a month [6].

In addition to buprenorphine, liquid crystal systems have been used in in-vivo and in-vitro studies based on sorbitan monooleate (SMO) for leuprolide acetate [7,8] and entecavir [9]. However, no studies have been reported on the preparation of a slow-release formulation of aripiprazole based on LLC. Given the reluctance of bipolar and schizophrenic patients, particularly children, to adhere to daily and frequent medication regimens, a monthly injection of the drug based on LLC could prove significantly beneficial for these individuals. Additionally, the slow-release LLC formulation can have favorable characteristics such as the lowest initial burst release, uniform release rate, minimum possible toxicity, and lowest production cost. Lyotropic liquid crystal systems are composed of amphiphiles that transform into cubic (Q2), hexagonal (HII), and lamellar (Lα) phases. Inverted hexagonal phases have been widely used to control the release rate of various drugs [10,11]. The crystal structures consist of the arrangement of lipid bilayers and aqueous channels with the minimum possible geometric shape, and this complex network of aqueous nanochannels in the mesophase plays an important role in the continuous release of drugs from liquid crystals [12,13].

In the present study, various LLC formulations containing aripiprazole were designed using PC, SMO, and derivatives of glycerol oleate (glycerol monooleate (GMO), GDO, glycerol trioleate (GTO) along with the NMP solvent. The optimal LLC formulations were selected based on minimum burst release and maximum release within 30 days. Furthermore, in vitro and in vivo evaluations of the formulations were conducted.