(W1130-01-01) Hydrogel-Forming Microneedles in Combination with Risperidone/Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Enhanced Transdermal Delivery Potential for the Treatment of Schizophrenia

Purpose: Schizophrenia is a brain disorder that affects up to 1% of the population (1). According to the World Health Organization (WHO), 200 million people are affected worldwide (2). It is the eighth leading cause of disability worldwide in people aged 15–44 years (3). It is characterized by several symptoms, such as delusions, hallucinations, disorganized speech or behavior and impaired cognitive ability. These symptoms occur due to an imbalance in neurotransmitters, including dopamine and serotonin (4). Risperidone (RIS) is an antipsychotic agent that is used for the treatment of schizophrenia and related disorders, as it has antagonistic effect on serotonin-5HT2 and dopamine-D2 receptors. It is available in both oral and injectable dosage forms. Its usual oral daily dose is between 4-6 mg, while the intramuscular dose is initially prescribed as 25 mg every 2 weeks (5). The clinical limitations of the commercially available oral and injectable dosage forms for the delivery of antipsychotic drugs may be potentially overcome by the administration via the transdermal route. Microneedles (MNs) are one of the most promising approaches for achieving systemic effects through transdermal drug delivery in a pain-free way. These devices are intended to be self-administering and self-disabling, preventing the production of contaminated sharps waste (6). The formation of inclusion complexes of RIS with hydroxypropyl-β-cyclodextrin (HP-β-CD) was used to enhance the solubility, which will potentially enhance the transdermal delivery in the presence of hydrogel-forming MNs.

Methods: RIS/HP-β-CD complexes were prepared by mixing the powders in a 1:1 molar ratio and dissolving the mixture in methanol. After that, the solvent was evaporated using vacuum oven at 40°C and -0.08 MaPa for 24 hrs. Complexes of 100 mg were weighed and compressed as tablets using a manual hydraulic press (Specac® Atlas, Specac Ltd, Kent, UK), by applying 4 tonnes for 30 seconds. To prepare MNs, a solution of 15% PVA (85-124 KDa), 10% PVP K30 and 1.5% citric acid was prepared in water. Then, 700 μl of the prepared gel were cast in 0.5 cm², 19 X 19 conical moulds. After that, the moulds were centrifuged for 15 mins at 5000 rpm to remove air bubbles and left to dry at room temperature for 48 hrs. Then, the sidewalls formed during moulding were carefully removed using scissors. The polymers were crosslinked at 130°C for 40 mins. The mechanical properties of the MNs were examined in terms of percentage height reduction by applying 32 N force for 30 secs using the Texture Analyser (Stable Microsystems, Haslemere, UK). The insertion properties were studied using 8 layers of Parafilm^TM as an alternative for neonatal porcine skin (7). Physicochemical properties of pure materials and RIS/HP-β-CD complexes were further studied using DSC and XRD. Ex vivo permeation and skin deposition studies of RIS, with and without the use of MNs were conducted using Franz cells and excised dermatomed neonatal porcine skin from stillborn piglets.

Results: RIS/HP-β-CD complexes tablets were successfully formed. The absence of the melting peak of RIS in the DSC thermogram and the lack of crystalline peaks in the XRD diffractogram of RIS/HP-β-CD complexes (Figure 1) indicate the conversion of the drug from crystalline to amorphous state. These results could also be attributable to RIS complexation inside the HP-β-CD (8). The casting method produced well-formed MNs (Figure 2). In terms of mechanical properties, these MNs showed 13.3% height reduction and reached the 3rd layer of Parafilm^TM after applying 32 N for 30 secs, which corresponds to 378 µm. In other words, these MNs can potentially reach the dermis layer of the skin. After 24 h, 4.63 ± 0.23 mg of RIS was delivered across the skin in the presence of MNs, while only 0.72 ± 0.66 mg was delivered in the absence of the MNs. It was also found that, after 24 h, the amount of drug deposited in the skin was 0.33 ± 0.07 mg and 0.47 ± 0.22 mg in the presence and absence of MNs, respectively (Figure 3).

Conclusion: This work presented the possibility of delivering RIS transdermally using MNs in a potentially patient-friendly manner. The complexation with CD may enhance the overall bioavailability of RIS when combined with hydrogel-forming MNs. Furthermore, permeation studies showed that the drug can be delivered throughout the skin in a statically significant higher amount in the presence of MNs. Also, it was found that some of the drug remained in the skin, which may lead to a sustained release of RIS for the treatment of schizophrenia. An in-vivo study will be conducted to study the delivery of RIS in a suitable animal model.

References: 1. Stepnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules. 2018;23(8).
2. WHO. Schizophrenia 2019.
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5. NICE. Risperidone 2018, June.
6. Paredes AJ, McKenna PE, Ramöller IK, Naser YA, Volpe‐Zanutto F, Li M, et al. Microarray patches: Poking a hole in the challenges faced when delivering poorly soluble drugs. Advanced Functional Materials. 2020;31(1).
7. Larraneta E, Moore J, Vicente-Perez EM, Gonzalez-Vazquez P, Lutton R, Woolfson AD, et al. A proposed model membrane and test method for microneedle insertion studies. International Journal of Pharmaceutics. 2014;472(1-2):65-73.
8. Jun SW, Kim MS, Kim JS, Park HJ, Lee S, Woo JS, et al. Preparation and characterization of simvastatin/hydroxypropyl-beta-cyclodextrin inclusion complex using supercritical antisolvent (SAS) process. Eur J Pharm Biopharm. 2007;66(3):413-21.

Acknowledgments: This PhD project has been funded by Jordan University of Science and Technology.

A) DSC and B) XRD of RIS, HP- β -CD, RIS/HP-B-CD PM and RIS/HP- β -CD CX.



A) Microscopic image for PVA/PVP/Citric acid MNs, B) MNs height before and after applying 32 N for 30 secs (Means + S.D, N= 60), C, D & E) 1st, 2nd and 3rd layers of ParafilmTM after MN insertion with a thumb, respectively.



Ex-vivo A) drug permeation (Means ± S.D, N= 3) and B) skin deposition in dermatomed neonatal porcine (Mean + S.D, N= 3).