Microneedle array patches for sustained delivery of fluphenazine: A micron scale approach for the management of schizophrenia

Schizophrenia is a severe chronic mental illness characterised by impaired emotional and cognitive functioning. To treat this condition, antipsychotics are available in limited dosage forms, mainly oral and injectable formulations. Although injectable antipsychotics were designed to enhance adherence, they are invasive, painful and require a healthcare professional to be administered. To overcome such administration issues, extensive research has been focused on developing transdermal antipsychotic formulations. In this work, three microneedle (MN) systems were developed to deliver fluphenazine (FLU) systemically. A decanoic prodrug of FLU called fluphenazine decanoate (FLUD) was used in two of the MN formulations due to its high lipophilicity. FLU-D was loaded into dissolving MNs and nanoemulsion (NE)-loaded MNs.

The parent drug FLU was loaded into poly(lactic-co-glycolic acid) (PLGA)-tipped MNs. All MN systems were characterised and evaluated in vitro and in vivo. The in vivo evaluation of the three developed MN systems showed their ability to deliver FLU into the systemic circulation, as the C_max of FLU-D dissolving MNs was 36.11 ± 12.37 ng/ml. However, the C_max of FLU-D NE loaded dissolving MNs was 12.92 ± 6.3 ng/ml and for FLU-PLGA tipped MNs was 21.57 ± 2.45 ng/ml. Compared to an intramuscular (IM) injection of FLU-D in sesame oil, the relative bioavailabilities were 26.96 %, 21.73 % and 42.45 % for FLU-D dissolving MNs, FLU-D NE dissolving MNs and FLU-PLGA tipped MNs, respectively. FLU plasma levels were maintained above the minimum human therapeutic limits for a week.

Highlights

• Current treatment for Schizophrenia mainly consist of oral and injectable formulations.
• Injectable antipsychotics, are invasive, painful, and require healthcare professionals.
• Microneedle (MN) systems were developed to deliver the fluphenazine transdermally.
• In vitro/in vivo studies of MNs were capable of delivering drug across the skin.
• MN could be a convenient and painless long-acting method for antipsychotics.

Consequently, these various MN formulations are considered to be a viable options for the transdermal delivery of fluphenazine and its prodrug. The three MN systems developed offer patients a user-friendly, painless, and convenient long-acting delivery method for FLU. Reducing dosing frequency and using less invasive drug administration methods can enhance adherence and foster positive therapeutic outcomes. This study demonstrates the capability and adaptability of MNs technology to transport hydrophobic molecules from the skin to the systemic circulation.

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Materials

Acetonitrile for high-performance liquid chromatography (HPLC), ammonium acetate, methanol for HPLC, bovine serum albumin (BSA), poly(vinyl alcohol) (PVA) (MW 10 kDa and 31–50 kDa), Tween®80, Tween®20, Pluronic®L-31 (PL®31), Pluronic®L-64 (PL®64), Nile red, sodium dodecyl sulfate (SLS), formic acid, sesame oil and sucrose were purchased from Sigma–Aldrich (Dorset, UK). Glycerol (Anala Rnormapur, 99.5 %) was purchased from VWR International (Leicestershire, UK). Fluphenazine decanoate was obtained from Manus Aktteva Biopharma (Gujarat, India). Disposable razor (Gillette Blue IITM, Gillette, Reading, UK). Poly(lactic-co-glycolic acid) (PLGA), a 50:50 M ratio of lactide:glycolide, inherent viscosity: 0.59 dl/g, Durect, Cupertino, (California, USA). Poly(vinyl pyrrolidone) (PVP) (MW 29–32 kDa), Ashland, (Kidderminster, UK). Dimethyl sulfoxide (DMSO) was provided by VWR International Limited (Leicestershire, UK). Piglets were provided by the Agri-Food and Bioscience Institute (Hillsborough, Northern Ireland, UK). Sodium hyaluronate was provided by Kewpie Corporation Shibuya-Ku (Tokyo, Japan). Fluphenazine hydrochloride was purchased from Chemos Sonnenring (Aldrich, Germany). Uranyl acetate was purchased from Ted Pella (Redding, USA). All other reagents were of analytical grade and purchased from standard commercial suppliers.

Juhaina M. Abu Ershaid, Lalitkumar K. Vora, Fabiana Volpe-Zanutto, Akmal H. Sabri, Ke Peng, Qonita K. Anjani, Peter E. McKenna, Anastasia Ripolin, Eneko Larrañeta, Helen O. McCarthy, Ryan F. Donnelly, Microneedle array patches for sustained delivery of fluphenazine: A micron scale approach for the management of schizophrenia, Biomaterials Advances, Volume 153, 2023, 213526, ISSN 2772-9508, https://doi.org/10.1016/j.bioadv.2023.213526.

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