Schizophrenia is a complex mental disorder characterized by psychosis, hallucinations, changes in consciousness and perception, a lack of interest, and cognitive deficits. It globally impacts approximately 24 million individuals worldwide [
1]. Collectively, these symptoms result in impaired functioning in various aspects of life, including work, school, and social interactions [
1,
2]. It ranks among the top ten causes of long-term disability and necessitates extensive mental health care. Individuals with schizophrenia often struggle to recognize their illness or the necessity for treatment, and this lack of insight is linked to various adverse outcomes. These include nonadherence to treatment, a heightened risk of relapse, more severe psychological symptoms, and an overall poor prognosis for the individual’s condition [
3]. Antipsychotic medications have notable limitations. Initially, their effectiveness is observed in approximately 50% of patients. Additionally, they are associated with significant metabolic side effects and can potentially result in issues like sexual dysfunction or agranulocytosis [
4]. One class of drugs to treat schizophrenia is atypical antipsychotics, which inhibit the HT2A serotonin receptor and dopamine D2 receptor. Lurasidone, classified as a novel atypical (second-generation) antipsychotic medication, has gained approval for the treatment of adult schizophrenia. Lurasidone is superior to other atypical antipsychotics as it exhibits the highest affinity for the 5-HT7 receptor, along with offering enhanced therapeutic advantages to treat schizophrenia. Further, it has a high safety profile due to the absence of cardiovascular side effects and limited adverse effects on weight or metabolic profiles [
5]. Lurasidone, when administered orally, undergoes extensive metabolism. As a result, only a substantial portion of the administered dose becomes available in the systemic circulation [
6]. Moreover, the cytochrome P450 enzyme CYP3A4 primarily metabolizes it, so care must be taken when co-administering it with drugs that induce or inhibit CYP3A4 [
7]. Also, patients with renal or hepatic dysfunction should adjust their doses [
8]. The transdermal delivery of lurasidone can eliminate these limitations and be a potential alternative for oral delivery. The skin is an attractive site for drug delivery due to its extensive surface area and accessibility [
9]. The skin, encompassing a surface area of about 1 to 2 square meters, is the body’s largest organ [
10]. Transdermal drug delivery systems are designed to deliver active ingredients through the intact skin into the systemic circulation. However, the stratum corneum, the outermost layer of the skin, acts as a barrier that only allows small, lipophilic molecules to pass through. This layer contains both hydrophilic and hydrophobic regions, and prevents the entry of foreign substances [
11]. Transdermal delivery offers several advantages, including maintaining a controlled amount of drug in plasma levels, reducing the risk of adverse effects, and eliminating hepatic first-pass metabolism [
12]. Microneedle technology is a type of transdermal delivery system that offers a less invasive and controlled method of drug delivery [
11]. Microneedles, characterized by their micron size needles, create micro-scale channels in the skin, effectively breaching the stratum corneum barrier without causing pain [
9]. These channels enable the delivery of a wide array of therapeutic agents, ranging from small molecules to macromolecules and biologics, into skin layers. This capability facilitates both localized and systemic treatments [
13]. Upon application to the skin, microneedles penetrate the epidermal layer and deliver compounds into the underlying dermis, which has high vascular and lymphatic circulation. This enables the systemic absorption of the drug, allowing for sustained and controlled release [
14]. Microneedles offer several advantages over traditional hypodermic needles, making them a promising technology in the realm of drug delivery. These benefits include reduced invasiveness, an ease of administration, and enhanced patient acceptance [
15]. Various types of microneedles exist, including hollow, biodegradable solid/dissolving, and other polymeric microneedles, which can be coated or loaded with the compound that is intended to be delivered [
14]. Dissolvable microneedle patches, composed of water-soluble polymers, are designed for disintegration after being inserted into the skin. These patches are commonly made using water-soluble polymers like polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). Their high solubility means that they can quickly dissolve upon contact with the interstitial fluid in the skin and release their content into skin layers, thus facilitating the transdermal delivery of drugs [
16]. Nanotechnology stands out as a rapidly expanding field, especially nanoparticles and nanomaterials [
17]. Nanoparticles are small, solid, spherical structures that are made from either natural or synthetic polymers. PLGA stands out as one of the most widely used biodegradable polymers with extensive applications in polymeric nanoparticle formulation due to its attractive properties. Firstly, its biodegradability and biocompatibility ensure its safety, and it has gained approval from both the FDA and the European Medicine Agency for use in drug delivery systems. Moreover, it offers protection to drugs from degradation. PLGA nanoparticles’ diverse utility comes from their ability to carry various types of therapeutic agents such as small-molecule drugs, whether they are hydrophilic or hydrophobic, and big molecular drugs, vaccines, and complex biological macromolecules [
18]. Nanoparticles play an important role in enhancing the bioavailability, solubility, and transdermal penetration of many drugs when compared to traditional topical formulations [
19]. Additionally, they can enable the delivery of the desired amount of a drug over a prolonged period [
20,
21]. When nanoparticles are incorporated into microneedles, they synergize with the advantages of microneedle technology, enabling an even more effective delivery of therapeutic agents [
22]. Nanoparticles can be efficiently delivered across the stratum corneum barrier by embedding them into the tips of microneedles that are then applied directly to the skin. Adding nanoparticles in microneedles can enable the delivery of both hydrophilic and hydrophobic drugs, which extends the scope of drugs that can be delivered transdermally [
23]. Researchers have explored the potential of these microneedle patches, which can gradually release nanoparticles, providing prolonged therapeutic effects. This innovation holds significant promise for long-acting self-administration in chronic conditions, potentially improving patient compliance compared to conventional daily pills or injections [
14].
The main aim of this study is to develop and evaluate a transdermal delivery system for lurasidone. This approach is designed with a dual purpose: firstly, to enhance the bioavailability of lurasidone, potentially reducing its side effect, and secondly, to increase patient adherence to the medication regimen. By considering the patch size, the oral dosage requirements, and the bioavailability percentage of lurasidone, our aim was to deliver 18 µg/cm2/day of the drug into the systemic circulation for a three-day period. The in vitro delivery of lurasidone with the help of chemical enhancers, Dr. PenTM Ultima A6, and microneedles was analyzed. We successfully achieved the transdermal delivery of a dose equivalent to 20 mg of oral lurasidone, using biodegradable microneedle patches loaded with lurasidone nanoparticles. These microneedles, fabricated with PVA and PVP polymers, detached from the patch with the use of an effervescent backing formula.