Nanosystems for Brain Targeting of Antipsychotic Drugs: An Update on the Most Promising Nanocarriers for Increased Bioavailability and Therapeutic Efficacy

Abstract

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. Nevertheless, adverse drug reactions jeopardize clinical outcomes, resulting in patient non-compliance. The design formulation strategies for enhancing brain drug delivery has been a major challenge, mainly due to the restrictive properties of the blood-brain barrier. However, recent pharmacokinetic and pharmacodynamic in vivo assays confirmed the advantage of the intranasal route when compared to oral and intravenous administration, as it allows direct nose-to-brain drug transport via neuronal pathways, reducing systemic side effects and maximizing therapeutic outcomes. In addition, the incorporation of antipsychotic drugs into nanosystems such as polymeric nanoparticles, polymeric mixed micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanoemulgels, nanosuspensions, niosomes and spanlastics, has proven to be quite promising. The developed nanosystems, having a small and homogeneous particle size (ideal for nose-to-brain delivery), high encapsulation efficiency and good stability, resulted in improved brain bioavailability and therapeutic-like effects in animal models. Hence, although it is essential to continue research in this field, the intranasal delivery of nanosystems for the treatment of schizophrenia, bipolar disorder and other related disorders has proven to be quite promising, opening a path for future therapies with higher efficacy.

Keywords: antipsychotics; bipolar disorder; brain targeting; intranasal delivery; nanocarriers; nanoparticles; nanosystems; psychotic disorders; schizophrenia.

Figure 1

Neuronal and systemic pathways of brain transportation of drugs following intranasal administration.

Figure 2

Types of nanosystems that have been used for the brain delivery of antipsychotic drugs.

Figure 3

(A) Transmission electron microscopy micrographs of the developed risperidone spanlastics; (B) Brain concentration vs time profiles of the intranasal risperidone spanlastics (“optimized formula”) and intranasal risperidone solution (“drug solution”); (C) Nasal sheep mucosa histopathological evaluation of the developed risperidone spanlastics (iii), compared to normal saline (negative control, (i)) and isopropyl alcohol (positive control, (ii)); adapted from Abdelrahman et al. [98], reproduced with permission from Elsevier [License Number 5477081208011].

Figure 4

(A) Scanning electron microscope image of the developed olanzapine SLN; (B) In vitro drug release profiles of the optimized formulations, Tween^® 80 coated SLN (“GLY NP”) and non-coated SLN (“C GLY NP”); (C) Effect of IV formulation administration, namely olanzapine Tween^® 80 coated SLN (“C GLY NP”), olanzapine non-coated SLN (“GLY NP”), olanzapine solution (“PURE OLN”), and drugless vehicle (“Vehicle control”), on animal body weight; adapted from Joseph et al. [100], reproduced with permission from Elsevier [License Number 5477090054162].

Figure 5

(A) In vitro drug release profile of the developed asenapine NLC (“GC-ANLC”) and a drug solution (“ASM”); (B) Cell viability results (A549 cells) of the developed asenapine NLC (“GC-ANLC”) and a drug solution (“ASM”); (C) Plasma (left) and brain (right) drug concentration vs time profiles of the developed asenapine NLC after IN administration [“GC-ANLC (i.n.)”], and after IV [“ASM(i.v.)] or IN [“ASM(i.n.)] administration of a drug solution; adapted from Singh et al. [105], reproduced with permission from Elsevier [License Number 5477090411361].

Figure 6

(A) Clozapine in vitro drug release profiles of the optimized clozapine nanosuspension and a conventional clozapine suspension; (B) Pharmacokinetic clozapine brain profiles after IN administration of the optimized nanosuspension and oral administration of a conventional suspension; (C) Histopathology images of nasal tissues after exposure to the optimized clozapine nanosuspension (left) and conventional clozapine suspension (right), compared to a control group (middle); adapted from Patel et al. [111], reproduced with permission from Elsevier [License Number 5477090677061].