Antipsychotic Nanomedicine: A Successful Platform for Clinical Use

Keywords::

• adverse effects
• bioavailability
• extended release
• paliperidone palmitate
• polymeric nanoparticles
• risperidone

Nanomedicine, the medical application of nanotechnology, has great potential to solve problems in medicine (i.e., to diagnose, treat and prevent diseases at cellular and molecular levels) [1]. The particle sizes of nanomedicines range between 1 and 1000 nm (1 µm), which include macromolecular materials, polymers, noble metals, carbon nanomaterials and inorganic nanoparticles. Mostly, diagnostic and/or therapeutic agents are adsorbed, entrapped, conjugated or encapsulated in nanomedicines for diagnosis and/or treatment [1–4]. The nanomedicines linked with targeting ligand(s) can bind with specific targets/receptors on the cell membrane for targeting/synergistic effects. Advanced nanomedicines are now being developed in order to target specific organelles within the cells [3]. The surface-modified nanomedicines (i.e., hydrophilic surfaces) using PEG or its derivatives in the size range of 100–200 nm are generally preferred in order to produce desirable or ideal in vitro/in vivo qualities, such as bioavailability enhancement, toxicity reduction, dose reduction, solubility enhancement, drug targeting and product stability [2–7].

The various adverse effects associated with antipsychotic agents are a great concern, and minimizing these side effects remains a challenge in drug delivery research [8–10]. The atypical antipsychotics, such as risperidone, paliperidone palmitate, haloperidol, olanzapine and clozapine have been predicted to exert their superior therapeutic action with fewer adverse effects compared with older antipsychotics, but their clinical use remains restricted to limited numbers of patients due to various adverse effects, such as weight gain, the development of diabetes and blood dyscrasias, among others. Indeed, dose reduction of antipsychotic drugs can be achieved by using nanomedicines of antipsychotic drugs. The administration of nanomedicines via the parenteral route has advantages such as the avoidance of first-pass metabolism, targeted drug delivery and sustained release. Here, the concept of parenteral administration is effective for haloperidol, in that 1.5–3 mg/day intramuscular therapy of haloperidol is equivalent to 6–12 mg/day oral therapy [10]. In recent years, cutting-edge developments in antipsychotic nanomedicine have shown their preclinical and clinical effectiveness for the therapy of psychotic disorders [9–11]. The development of antipsychotic nanomedicine for bioavailability enhancement, extended drug release, dose reduction and toxicity reduction has been claimed as a novel idea [8,10]. The most successful antipsychotic nanomedicine platforms include polymeric nanoparticles, solid lipid nanoparticles (SLNs), nanocapsules, nanoemulsions, drug nanocrystals and micelles. Since 2009, Invega Sustenna^® (Janssen Pharmaceuticals Inc., NJ, USA), a nanomedicine (nanocrystal) product, has been commercially available for the treatment of psychosis. It is administered once monthly as a depot intramuscular (long-acting) injection [9]. This article will focus on the importance of antipsychotic nanomedicines loaded with drugs such as risperidone, paliperidone palmitate, haloperidol, olanzapine and clozapine and discuss their preclinical and clinical potential for the treatment of psychotic disorders.

Risperidone & paliperidone palmitate nanomedicines

Risperidone is an antipsychotic drug that is used for the treatment of psychotic disorders. The drug was approved by the US FDA as an atypical antipsychotic drug since it produces fewer extrapyramidal side effects compared with conventional antipsychotics. It produces dose-dependent extrapyramidal side effects. In order to reduce these dose-dependent adverse effects, the low and safest dose is recommended for treatment. Owing to first-pass metabolism, low oral bioavailability is reported for risperidone, with a short half-life of 3 h. Furthermore, the nontargeted delivery of risperidone results in numerous adverse effects [8,10]. In order to avoid these drug delivery issues, risperidone-loaded nanoparticles of biodegradable polymers, such as poly(∊-caprolactone), poly(d,l-lactide-co-glycolide) and poly(d,l-lactide), were prepared by the nanoprecipitation method and characterized for in vivo effectiveness. In mouse models, risperidone-loaded nanoparticle formulations prolonged the antipsychotic effects with fewer adverse effects. This is possibly owing to the accumulation of its active metabolite (9-hydroxy-risperidone) and changes in the pharmacokinetic profile. It has been suggested that the maintenance of risperidone plasma concentration using nanoparticle administration by the intravenous route may enhance the biodistribution and bioavailability of risperidone for improved pharmacotherapy. However, further studies are required in order to understand the mechanism of adverse effects reduction [8,10–12]. Later, SLNs showed advantages over biodegradable polymeric nanoparticles in terms of brain targeting, high drug payload and biocompatibility. Considering these advantages, risperidone-loaded SLNs were prepared in order to achieve brain-targeted antipsychotic therapy. The pharmacodynamic properties of risperidone-loaded SLNs were studied by paw test using a Perspex platform, and the results showed an improvement in hindlimb retraction time values in comparison with risperidone solution, indicating the brain-targeting effect of risperidone-loaded SLNs over the risperidone solution. Furthermore, the pharmacokinetics, biodistribution and imaging studies of risperidone-loaded SLNs in animal models showed an enhancement of the brain:blood ratio and brain drug localization [13].

Paliparidone palmitate is another atypical antipsychotic drug. Chemically, it is a palmitate ester of paliparidone, which is a major active metabolite of risperidone. It requires solubilizers such as PEG 4000 and polysorbate 20 for the solubilized release of the drug from the formulation. d-α-tocopheryl PEG 1000 succinate (TPGS) is reported as being a micelle-forming material with valuable solubilization properties. In order to improve the solubilized release of paliparidone palmitate by using a nanoplatform, Muthu et al. prepared and evaluated paliparidone palmitate-loaded TPGS micelles, which showed improvements in antipsychotic effects [14]. The sustained antipsychotic effects and modified release patterns of paliperidone palmitate micelles suggested the utility of TPGS micelles for the effective and safe treatment and short-term management of psychotic disorders [14].

Haloperidol nanomedicine

Haloperidol is one of the most commonly and widely used antipsychotic drugs for the treatment of psychotic disorders. The chronic use of haloperidol leads to severe motor side effects (e.g., abnormal movements such as oral dyskinesia, neurotoxicity and oxidative stress in extrapyramidal brain regions). It was reported recently that haloperidol nanomedicine can produce better therapeutic effects with longer durations of action. The d,l-amphetamine-induced stereotyped movements were quantified and the nanocapsules of haloperidol demonstrated greater pharmacotherapy than the free drug. The acute motor side effects were also reduced (i.e., catalepsy and oral dyskinesia) [15]. Furthermore, the pharmacokinetic pattern, organ biodistribution and drug accumulation in the brain dopaminergic areas need to be studied in order to prove the selectivity and targeting nature of haloperidol nanomedicine. In order to overcome haloperidol-induced movement disorders (i.e., adverse effects), haloperidol-loaded, polysorbate-coated nanocapsule suspensions containing fish oil (rich in n-3 fatty acids) were prepared and evaluated for oxidative stress and antioxidant defense parameters. The haloperidol nanomedicine minimized the motor side effects, as well as oxidative damage in the extrapyramidal brain regions. In future, haloperidol nanomedicine could be utilized in psychiatry in order to reduce adverse effects and improve the quality of life of psychiatry patients [16].

Olanzapine & clozapine nanomedicines

Olanzapine is an atypical antipsychotic drug that has been approved by the FDA for the management of schizophrenia and for the treatment of moderate-to-severe mania associated with bipolar disorders [17]. The drug suffers from hepatic first-pass metabolism and poor brain permeability owing to P-glycoprotein efflux. Higher dosages of olanzapine are commonly associated with extrapyramidal effects, orthostatic hypotension, hypercholesterolemia, weight gain, dry mouth, tremors, akathisia and somnolence. In order to overcome some of these problems, olanzapine-loaded, biodegradable, polymeric, lipid core nanocapsules were developed. A prolonged antipsychotic action was observed by d,l-amphetamine-induced stereotyped behavior in an animal model [17]. The studies showed a significant reduction in weight gain and total cholesterol levels in comparison to free olanzapine. This work additionally provided a promising proof of concept for the clinical study of olanzapine nanomedicine [17]. SLNs play a major role in the bioavailability enhancement and brain targeting of antipsychotic drugs. For example, Manjunath and Venkateswarlu have worked on another atypical antipsychotic drug, clozapine, which is frequently used for the treatment of schizophrenia [18]. They evaluated the pharmacokinetics/biodistribution of clozapine-loaded SLNs in rats and mice. It was found that the nanomedicine formulation significantly enhanced the bioavailability and brain distribution of clozapine in comparison with the clozapine suspension [18]. These results suggest the possibility of using clozapine nanomedicine in clinical settings with better bioavailability and brain targeting. The major advantages of using clozapine nanomedicine (solid lipid based) will be for the greater delivery of clozapine into the brain and for reducing peripheral drug toxicity.

Conclusion & future perspective

‘Nanopsychiatry’ is a novel term that is used to emphasize the importance of combining psychiatry with nanomedicine [19]. Invega Sustenna, which is a commercially available nanomedicine (nanocrystals of paliperidone palmitate) used in psychotic patients for the treatment of psychosis, demonstrates the clinical success of nanomedicine development for the treatment of psychotic disorders [9]. Recent research shows the promising results of antipsychotic nanomedicine (e.g., risperidone polymeric nanoparticles, haloperidol nanocapsules, clozapine nanoparticles and paliperidone palmitate micelles, among others) for bioavailability enhancement, dose reduction, extended and controlled drug release and toxicity reduction. In future, the development of theranostic antipsychotic nanomedicines combining both antipsychotic drugs and diagnostic moieties may enable physicians to detect and assess brain signaling pathways of psychotic disorders and treat them simultaneously [20].

Financial & competing interests disclosure

MS Muthu acknowledges the Science and Engineering Research Board (SERB), New Delhi, India, for the research project under the fast track scheme for young scientists (OYS); the project file number is SR/FT/LS-132/2011. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

MS Muthu acknowledges the Science and Engineering Research Board (SERB), New Delhi, India, for the research project under the fast track scheme for young scientists (OYS); the project file number is SR/FT/LS-132/2011. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.