3D-printed cannabidiol hollow suppositories for treatment of epilepsy

Epilepsy is a chronic and progressive neurological disorder characterized with recurrent, paroxysmal, and stereotypical seizures, which greatly affects the quality of patient life (Wu et al., 2022). Moreover, several typical comorbidities such as depression, anxiety, motor impairment, and cognitive deficits, decline the prognosis effect associated with the disease (Shin et al., 2023). About 0.4 %-1% of people worldwide live with epilepsy and antiseizure drugs (ASDs) are the initial option and the mainstay in epilepsy treatment (Sillanpää and Schmidt, 2017). But over 1/3 of the patients with medically refractory epilepsy are considered insensitive to current ASDs (Dwivedi et al., 2017, Löscher et al., 2013). Currently available ASDs are further prone to induce a variety of adverse effects on athletic ability and cognition (George et al., 2015). Therefore, ASDs with milder adverse effects are urgently needed for clinical therapy.

Cannabis has been medically used for thousands of years to treat symptoms such as depression, inflammation, and pain (Friedman and Sirven, 2017, Russo, 2017). Cannabidiol (CBD) is derived from cannabis with antiseizure effects and no psychoactive activity and addiction. The efficacy of CBD in treating various types of seizures has been demonstrated in animal seizure and epilepsy models (Huang et al., 2024, Mazurkiewicz-Bełdzińska and Zawadzka, 2022), the mechanisms of which include regulation of the targets in the brain (Mannucci et al., 2017), and modulation of gut microbiota (Gong et al., 2022). The only one oral formulation of CBD (Epidiolex^@, GW Research), approved by the United States Food and Drug Administration, is widely used to alleviate the Dravet syndrome or Lennox-Gastaut syndrome (Devinsky et al., 2017). However, oral CBD has prominent first-pass effect, leading to low oral bioavailability (Franco and Perucca, 2019).

Rectal drug delivery systems are commonly used for localized drug delivery and also for systemic treatment (Purohit et al., 2018). Moreover, the rectal route of drug administration has been widely applied in the treatment of epilepsy, reducing the adverse effects of ASDs and seizure frequency (Vuong et al., 2021). Suppositories are a typical rectal drug delivery system, the typical shapes of which include bullets and torpedoes (Ham and Buckheit, 2017). Children, the elderly, and patients who are vomiting or unconscious can benefit from suppositories (Ban and Kim, 2013). However, conventional suppositories are easily excreted with feces and rapidly broken and lost after melting (Lamb et al., 2019). Patients typically need to take additional measures to solve the above problems, including frequent administration per day, multiple suppositories per administration, and complete defecation before the use of rectal suppositories (Boyle et al., 2015). However, these measures may be ineffectual when several defecations exist in a day for some patients, especially children. Therefore, conventional suppositories are not effective in slow release and high bioavailability due to the frequent defecation of children (de Boer et al., 1982). A long-term, locally retentive CBD rectal preparation is imminently required.

Three-dimensional (3D) printing is emerging in pharmaceutical manufacturing and widely applied in preparation of dosage forms suitable for various drug delivery routes, such as oral, rectal, vaginal, parenteral, and implantable applications (Dumpa et al., 2021, Mancilla-De-la-Cruz et al., 2022). In our previous study, we designed a mesalazine (MSZ) hollow suppository (MHS) followed by 3D printing for the treatment of ulcerative colitis (Wei et al., 2023). The MHS consists of an inner spring for support and an outer curved hollow shell containing MSZ, which can remain in the rat rectum for 5 h without obstruction of defecation. We regard this formulation may also be suitable for the systemic delivery of drugs for the therapy of other diseases than gut diseases.

Here, we designed a CBD-loaded hollow suppository (CHS) to achieve the systemic delivery of CBD by rectal administration. To our knowledge, this is the first report of a 3D-printed drug-loaded suppository for the treatment of epilepsy. The therapeutic efficacy of CHS was studied using the epileptic rat models, involving nerve cell recovery, and the improvement of gut microbiota, reactive oxygen species (ROS), and inflammation levels. The hollow structure improves the compliance of patients, especially children, in spite of their frequent defecation, and the rectal administration can avoid the first-pass effect of oral CBD and decrease the dosing frequency. The use of CHS may become an effective way against epilepsy.