Percutaneous transport of psychotropic agents

Journal of Drug Delivery Science and Technology 39 (2017) 247e259

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Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst

Percutaneous transport of psychotropic agents Kevin Ita College of Pharmacy, Touro University, Mare Island-Vallejo, California, CA 94592, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 January 2017 Received in revised form 31 March 2017 Accepted 3 April 2017 Available online 4 April 2017

Treatment rates for mental and substance abuse disorders are low, particularly in low and middleincome countries (LMICs), where treatment gaps of more than 90% have been documented [1]. Psychiatric disorders are particularly debilitating. One of the ways of improving pharmacotherapy of patients suffering from schizophrenia, depression, bipolar disorder and other psychiatric conditions is through the use of transdermal drug delivery systems (TDDS). The advantages of TDDS include avoidance of first-pass effect, the possibility of providing sustained release and improving patient compliance. There are several techniques available for facilitating the percutaneous transport of medications across the skin. These include prodrugs, chemical penetration enhancers, transfersomes and proniosomes. This review discusses advances made in the transdermal delivery of psychotropic medications. © 2017 Elsevier B.V. All rights reserved.

Keywords: Drug delivery Transdermal Psychotropic Iontophoresis Liposomes

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 1.1. Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 1.2. Major depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 1.3. Persistent depressive disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 1.4. Attention Deficit/Hyperactivity Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 1.5. Subthreshold forms of bipolarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1.6. Anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1.7. The human skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1.8. Advantages of transdermal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1.9. Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 1.10. Chemical penetration enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 1.11. Niosomes and proniosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 1.12. Elastic liposomes (transfersomes®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 1.13. Iontophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 1.14. Microneedles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 1.15. Transdermal delivery of psychotropic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 1.16. Asenapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 1.17. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 1.18. Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 1.19. Chlorpromazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 1.20. Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 1.21. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 1.22. Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 1.23. Alprazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 1.24. Transdermal drug delivery systems loaded with psychotropic medications and approved for clinical use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jddst.2017.04.009 1773-2247/© 2017 Elsevier B.V. All rights reserved.

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

1. Introduction Mental disorders affect a large percentage of the global population and lead to significant morbidity, mortality, and disability [2]. In 2010, mental and substance disorders accounted for 7.4% of global disability-adjusted life years (DALYs) and 22.9% of global years lived with disability (YLDs), making them the fifth leading cause of DALYs and the leading cause of YLDs [3]. In 2013, nearly 1 in 5 adults (an estimated 43.8 million people) aged 18 or older (18.5%) had a mental illness in the USA and 4.2% had a serious mental illness (SMI) [4]. The main psychiatric disorders are schizophrenia [5], depressive disorders [6,7], attention deficit/hyperactivity disorder [8], unipolar and bipolar affective disorders [9] and anxiety disorders [10-12]. 1.1. Schizophrenia It has been suggested that schizophrenia is probably the most severe type of psychiatric disorder [5]. The disease affects approximately 21million people globally [13] and is the third most disabling illness of the central nervous system worldwide with a global cost of 23.7 million disability-adjusted life years (DALYs) [5]. In the United States, 0.7% of the US population, or roughly 2 million Americans suffer from the disease [14]. Schizophrenia is characterized by positive symptoms (hallucinations and delusions), negative symptoms (socially withdrawn behavior), cognitive dysfunction, and affective dysregulation [15]. Other symptoms of this disease include formal thought disorder and disorganized or abnormal motor behavior [5]. Patients suffering from schizophrenia display cognitive deficits which affect processing speed, attention, working memory, verbal learning, visual memory, and executive functioning [16]. The etiopathogenesis of this complex, highly heritable and polygenic neuropsychiatric disease is yet to be ascertained [17] but a vertiginous array of abnormalities of varied neurotransmitters, cell types, brain regions and epidemiologic associations is thought to be implicated [18]. Most studies seek to integrate the roles of genetic liability, neurodevelopmental anomalies, aberrant synapse function, and environmental factors such as neonatal infections and substance use, yet the manner in which these distinct factors coalesce into the neurobiology of schizophrenia remains unclear [18]. It has been recently reported that several microRNA (miRNA), including microRNA 7 (miR-7), are expressed differentially in the postmortem prefrontal cortex of schizophrenia patients in comparison with healthy controls [19]. An increasing body of evidence has also found increased oxidative stress in patients suffering from schizophrenia, including in subjects who have never taken antipsychotic drugs [18]. Autoimmune mechanism is also thought to be involved in the pathogenesis of schizophrenia [17]. 1.2. Major depressive disorders Major depressive disorder (MDD) is a complex mental disorder with the following symptoms -persistent and pervasive low mood, including low self-esteem, loss of interest or pleasure, and feelings of personal worthlessness [20]. There is still a lack of a clear understanding of the neuropathological changes associated with this illness [21]. However, the monoamine hypothesis of depression

continues to dominate the field [21]. According to this postulate, there is an imbalance in monoaminergic neurotransmission which is causally related to the clinical symptoms of depression [21]. The lifetime prevalence of MDD is around 15%, which makes it one of the most prevalent mental disorders [20]. Increasing evidence from behavioral and neuroimaging studies has linked MDD to major disruptions in all reward related processes, including reward anticipation, motivation and outcome [22]. The disturbed reward processing in MDD patients is linked to disconnections within mesolimbic striatum-based reward circuitry [22]. Lower functional connectivity (FC) has been shown in the ventral tegmental area (VTA), striatum, and ventromedial prefrontal cortex (VMPFC), and weakened responsiveness to repetitive transcranial magnetic stimulation treatment of the dorsomedial prefrontal cortex (DMPFC) has been observed in MDD patients [22]. Neuroimaging studies into adult MDD have revealed dysfunction in frontal regions including medial, orbital, dorsolateral (dlPFC) and ventrolateral prefrontal cortex (vlPFC) as well as the anterior cingulate cortex (ACC) [7]. 1.3. Persistent depressive disorder Persistent depressive disorder (PDD) or dysthymic disorder (DD) tends to have milder symptoms and a chronic course compared to MDD, but with similar functional impairment [23]. This condition is characterized by persistent sad and/or irritable mood for a period lasting one year or longer [7]. DD may best be considered as being at the lower end of a depressive spectrum with less severe but more persistent symptoms [7]. The change of label from DD to PDD is a reflection of this dimensional approach [7]. The utility for pharmacotherapy for PDD is often debated, as the impaired mood, interpersonal dysfunction, and anhedonia often seen in PDD patients are frequently perceived as characterological deficits, not as symptoms [23]. 1.4. Attention Deficit/Hyperactivity Disorder Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterized by inattention, hyperactivity and impulsivity [8]. It is postulated that there is dysregulation of fronto-striatal circuits and the neurotransmitters involved in these pathways in ADHD patients [8]. In particular, emerging data implicate altered dopamine signaling [8]. There are three subtypes of ADHD, one marked by predominantly inattentive symptoms (ADHD-I), the second by hyperactivity and impulsiveness (ADHD-H), and the third displays a combination of inattentiveness and hyperactivity (ADHD-C) [24]. ADHD occurs in 6e8% of children and 2e3% of adults [25]. Although the exact causes of ADHD are unknown, the interplay between primary biological and secondary environmental risk factors plays an important role in this disorder [24]. A variety of genetic-environmental interactions have been implicated in ADHD, particularly those involving dopamine, such as DAT1, a dopamine transporter gene [24]. In addition, ADHD imaging studies showed cortical changes, including reductions in size and functional activity in the prefrontal cortex, as well as abnormalities in dopamine transport [24]. There are also reports showing that the noradrenergic system is involved in ADHD [26]. Neuropsychological and

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imaging studies have shown that ADHD is associated with alterations in the prefrontal cortex (PFC) and related circuits, and noradrenergic neurotransmitter systems are thought to play important roles in this area of the brain [26]. Some of the cardinal features of ADHD include deficits in executive functioning and alterations in motivation and reward [24]. 1.5. Subthreshold forms of bipolarity The inclusion of subthreshold forms of bipolarity (referred to as “Other Specified Bipolar and Related Disorder”) in the fifth edition of the Diagnostic and Statistical Manual of psychiatric disorders (DSM-5) has led to the debate regarding whether major depressive disorder and bipolar disorder are distinct and easily distinguishable diagnostic entities [27]. It has, however, been suggested that patients suffering from unipolar depression may tend to exhibit higher rates of anxiety, insomnia, loss of appetite and somatic complaints [27]. On the other hand, bipolar depression may be associated with higher rates of atypical features, psychotic symptoms, melancholic features, agitation, psychomotor disturbance and suicidal ideation [27]. Bipolar I disorder is a serious psychiatric condition characterized by the occurrence of one or more manic episodes with early onset (most often in the second decade of life) and is associated with chronic course [28]. 1.6. Anxiety disorders Anxiety disorders (AD) are characterized in part by heightened sensitivity to unpredictable future threat, which is manifest across diverse cognitive, affective, physiological, and behavioral symptoms [29]. There are various types of AD-social anxiety disorder (SAD), and panic disorder (PD). SAD is a persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others [30]. Panic disorder (PD) is the most common anxiety disorder, which is characterized by recurrent and unexpected panic attacks, and the lifetime prevalence of panic disorder is 3.4e4.7% [31]. The above-mentioned range of psychiatric disorders is by no means exhaustive. Transdermal administration of psychotropic medications is especially important as adherence to treatment is a challenge for patients [32]. 1.7. The human skin The skin is a complex organ and represents the body's first barrier to exogenous substances [33]This organ provides major physiological functions such as regulation of the body temperature, hydration, as well as the protection against the ingress of external agents [34]. The skin is composed of the epidermis (a barrier made of epithelial cells), the dermis (a connective tissue that supports the epidermis) and the hypodermis (an adipose tissue) [34]. The outermost layer of the epidermis is the stratum corneum (SC) which has a simple two compartment structure [35]. It is made up of corneocytes (approximately 30 mm by 0.5e0.8 mm thick cells) which are filled with keratin and lack nuclei and cytoplasmic organelles [36]. There are 10e50 cell layers in the human SC with an intercellular spacing of about 20 nm [36]. The stratum corneum prevents many medications from entering the bloodstream in therapeutic quantities [33]. The viable epidermis comprises mainly keratinocytes (90%) while the remaining 10% of the cells are represented by Langerhans Cells (LC), melanocytes and mast cells [37]. The dermis is the structural component of skin and gives it the mechanical response required for protection [38]. This layer of the skin (dermis) is an arrangement of wavy fibers, 2e10 mm in crosssection, which are made of randomly oriented fibrils of ~100 nm

249

in diameter [38]. The dermis is composed of collagen (80e90% of dermis) and elastin (3e6%) - principal proteins responsible for the mechanical properties of the skin [38]. The extracellular matrix of the dermis has other biomolecules such as proteoglycans and glycoproteins [34]. It is generally accepted in the scientific community that the major barrier to percutaneous drug delivery is provided by the stratum corneum. Transdermal drug delivery research has focused on developing techniques to overcome this elegant and formidable architecture. There are three major mechanisms of percutaneous transportd through hair follicles with associated sebaceous glands, via sweat ducts, or across continuous stratum corneum between these appendages [39]. 1.8. Advantages of transdermal drug delivery Interest in percutaneous transport is due to the enormous advantages derived from this mode of drug administration. The transdermal drug delivery route has obvious advantages. Apart from providing effective systemic drug concentrations, this mode of drug administration avoids the preystemic metabolism and can sustain plasma levels within the therapeutic window for a prolonged period of time [40]. In addition, percutaneous drug administration is well accepted, easy to apply and is a good alternative to oral administration especially in clinical cases when the patient cannot swallow (or is in a coma) [40]. Transdermal drug delivery also avoids erratic absorption, nausea, and vomiting which may occur with oral drug administration [40]. However, not all psychotropic drugs can be formulated as transdermal drug delivery systems. A compound must satisfy certain criteria for it to be formulated into a transdermal patch. These include having an optimal partition coefficient, molecular weight, solubility and daily dose. Nevertheless, several techniques have been developed to enhance the percutaneous transport of psychotropic drugs. These include prodrugs, chemical penetration enhancers, nanocarriers (transfersomes, proniosomes), iontophoresis [41-43], sonophoresis [44,45], and microneedles [46]. 1.9. Prodrugs The use of prodrugs continues to attract significant attention as one of the approaches for enhancing transdermal drug penetration. Prodrugs are substances of a low or non-existent biological activity which become active following chemical or enzymatic biotransformation [47]. Prodrugs can be designed to increase the solubility and/or permeability of a compound resulting in transdermal flux enhancement [48]. With this approach, amino acid esters or amides (ionizable groups) can be introduced into the hydroxyl, thiol, amine, or carboxylic acid functionalities of the parent drug molecule to increase aqueous solubility [48]. The release of the active substance from the prodrug can take place before, during or after its absorption and occasionally, after it reaches the target [47]. Most prodrugs are carrier-linked prodrugs. These are compounds obtained as a result of a simple modification to the functional group of an active substance made by creating ester, amide, carbonate, carbamate, oxime, phosphate, N-Mannich base, imine or PEG (polyethylene glycol) conjugate [47]. The rationale for utlilizing prodrugs is that pharmacokinetic properties (absorption, distribution, metabolism, elimination) of medications can be optimized. Significantly, the prodrug strategy can also be used to increase the selectivity of drugs for their intended target leading to improved drug efficacy and reduced side effects [48]. A modern approach to the use of prodrugs for transdermal drug delivery is based on the fact that although the SC is a predominantly lipid barrier, the intercellular multilamellar bilayers that comprise that lipid barrier comprise alternating lipid and

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aqueous phases across which a permeant must traverse [48,49]. The consequence is that increases in both water (SAQ) and lipid (SLIPID) solubilities, or a balance of the two, are important to optimize transdermal transport of a prodrug [48,49]. 1.10. Chemical penetration enhancers Chemical penetration enhancers (CPE) are compounds which are utilized for transcutaneous flux enhancement [50,51]. CPEs are classified into those which decrease drug diffusion coefficient by disrupting the stratum corneum, those capable of increasing drug solubility) by transiently changing the solubility parameter of the skin [52], increasing partition coefficient or decreasing ‘skin thickness’ through a permeation shortcut [51,53]. Some CPES such as isopropyl myristate, oleic acid and linoleic acid act by fluidizing the skin lipid domain thereby increasing the diffusion coefficient of the penetrant while simple solvents, such as propylene glycol, ethanol, and Transcutol, facilitate drug solubility [52,54]. From a mechanistic standpoint, the application of some fatty acids (FA) on the skin surface can cause the redistribution of native FAs not only in the stratum corneum layer of epidermis but also in the lipid content of full epidermis and dermis layers [54]. Chemical enhancers possess numerous advantages including formulation flexibility, easy processing and low cost [50]. Interestingly, numerous structure-activity relationship (SAR) studies have shown that the enhancing activity of enhancers mainly depends on their chemical structures [50]. Despite the obvious advantages, CPEs also have limitations. Chemical enhancers have to meet certain criteria if they are to be used successfully for transdermal drug delivery [51]. They must not only enhance the transdermal delivery of medications at therapeutic rates but must do so without causing irritation or being cytotoxic [51]. 1.11. Niosomes and proniosomes Niosomes are vesicles formed by self-assembly of non-ionic surfactants and capable of encapsulating drug molecules with a wide range of solubility [55,56]. These are thermodynamically stable liposome-like vesicles formulated through the hydration of cholesterol, charge-inducing components such as charged phospholipids (e.g., dicethylphosphate and stearyl amine) and non-ionic surfactants (e.g., monoalkyl or dialkyl polyoxyethylene ether) [57]. They have been used to deliver hydrophobic and hydrophilic medications [55]. These vesicles can entrap hydrophilic drugs within the core and lipophilic ones can be retained in the hydrophobic domains [57]. Niosomes behave like liposomes, prolonging the circulation time of the entrapped drug and altering its organ distribution as well as metabolic stability [58]. But unlike liposomes, niosomes have higher chemical stability due to the incorporation of the surfactants, which are not easily hydrolyzed or oxidized like phospholipids [55]. Additionally, niosomes do not require special preparation and storage conditions, and are therefore relatively cost-effective and more attractive for industrial manufacturing than liposomes [59]. It has been postulated that niosomes increase the transcutaneous flux of medications through two proposed mechanisms: penetration enhancer effect of the nonionic surfactants or vesicleeskin interactions [55]. Despite widespread use in transdermal drug delivery, there are still concerns regarding the chemical stability of niosomes. These include physical and chemical instability, leakage and fusion of encapsulated drug from the vesicles, as well as hydrolysis of the encapsulated drug which can result in decreasing shelf life [59]. Some of these problems can be solved when proniosomes are used. Proniosomes are provesicles of non-ionic surfactants which can be

hydrated immediately before use to form niosomes [58]. Proniosomes can exist either as crystalline compact proniosomal gels, alcoholic solutions of the non-ionic surfactant or dry granular powder [59]. Proniosome powders have been prepared from span 60/cholesterol and four different carriers, namely maltodextrin, mannitol, lactose and pullulan [60]. 1.12. Elastic liposomes (transfersomes®) Elastic liposomes (also called transfersomes®) are formulated from phospholipids like conventional liposomes but differ from the later because they contain surface active agents which act as edge activators and impart elasticity and deformability to the liposomes [61,62]. Elasticity in these vesicles is attributed to the presence of an edge activator, which is a single chain surfactant with a high radius of curvature, capable of weakening the lipid bilayers of the vesicles and increasing their deformability and flexibility. It has been postulated that transfersomes® can cross many barriers through the apertures that would be limiting for other colloidal dispersions of similar size [63,64]. This is apparently due to the self-adaptable and extremely high flexibility of these vesicles [61,64]. Several reports in the literature have described elastic liposome or transfersome®, as a vesicle which can pass through the stratum corneum and increase the percutaneous penetration of drugs from the application site on the skin to the deeper dermal layers or the bloodstream [62]. This property is linked to hydration gradient [65]. According to this postulate, the most obvious natural transdermal gradient originates from water activity difference across the stratum corneum [65,66]. This gradient acts simultaneously on all vesicle ingredients. Transdermal hydration difference therefore creates very strong force acting on the skin through the vesicles and widening the weakest intercellular junctions in the barrier and creating 20e30 nm wide transcutaneous channels [6567]. Despite the plethora of reports in the literature attributing enhanced transdermal drug delivery to transfersomes, the ability of intact elastic liposomes to cross the stratum corneum and reach the deeper layers of the skin is still controversial [62]. 1.13. Iontophoresis Iontophoresis uses low-level electric current (approximately 0.5 mA) to enhance the transport of ionized and neutral molecules across the skin [42]. Direct current (DC) iontophoresis is considered to be the efficient as the amount of drug molecules delivered is directly proportional to the total amount of current crossing the skin [42]. Electromigration and electrosmosis are the major transport mechanisms in iontophoresis [43]. With electromigration, the transport of cationic drugs is enhanced from the anode compartment into the skin, and that of anionic drugs is delivered from the cathode [68]. Electroosmosis is the major transport mechanism of uncharged molecules and of high molecular weight cations [69]. Electrosmosisis is the convective movement of water by electric current and is beneficial for neutral molecules which do not dissociate into ions upon application of an electric current [70]. 1.14. Microneedles Microneedles lengths ranging from 25 mm to 2000 mm and can be used to disrupt the SC and form micro-scale drug delivery channels without touching the nerve fibers and blood vessels that are located in the epidermis and the dermis [71]. Microneedles can be fabricated from a wide range of materials including stainless steel [72], silicon [73], polymers [74] and ceramic materials [75].

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1.15. Transdermal delivery of psychotropic agents The use of transdermal patches for the delivery of therapeutic agents used for the management of psychiatric disorders is less studied and underinvestigated [76]. This is somewhat paradoxical because adherence to prescribed psychiatric and nonpsychiatric medication poses a serious challenge in people with mental illness and this can contribute to poor health outcomes [76]. Recently, transdermal patches have been approved for the management of certain psychiatric conditions including attention deficit hyperactivity disorder (Daytrana®) [77] and depression (Emsam®) [78]. The use of orally administered MAO inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of tyramineprovoked events (eg, acute hypertension and headache, also known as the “cheese reaction”) when combined with dietary tyramine. One of the advantages of selegiline transdermal patch is that it is the only MAOI available in the US for the management of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 h [78]. The purpose of this review is to discuss the influence of the different enhancement techniques on the transdermal delivery of psychotropic medications. Some of the methods used by investigators are shown in Table 1.

1.16. Asenapine Asenapine maleate (ASPM) is an atypical antipsychotic agent commercially available in the form of sublingual tablets [13]. It is used for the management of manic or mixed episodes in patients suffering from schizophrenia and bipolar I disorder [13]. Asenapine acts as an antagonist at both dopamine (D)-2 and serotonin (5-HT)2A receptors [14]. Following sublingual administration of a single 5mg sublingual dose, absolute bioavailability of ASPM was found to be 35% [14]. Extensive metabolism makes the oral route inconvenient for ASPM [13]. Recently, Shreya and coworkers studied the influence of transfersomes and chemical penetration enhancers on the percutaneous transport of ASPM [13]. Ultraflexible transfersomes were prepared from soy phosphatidylcholine (SPC) and sodium deoxycholate (SDC) [13]. The authors carried out in vitro skin permeation study for selected ASPMloaded transfersome formulations and reported transdermal flux values of 7.98 ± 0.41, 6.39 ± 0.30, and 6.95 ± 0.21 mg cm2 h
1, for

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formulations AT-2, AT-5, and AT-8 respectively [13]. The drug:SPC:SDC ratio for formulations AT-2, AT-5, and AT-8 were 5:75:10, 5:85:10 and 5:95:10 respectively [13]. Correspondingly, the flux values for the donor ASPM solutions at different pH values were 2.96 ± 0.22, 2.72 ± 0.20 mg cm2 h
1 at the pH of 4.5 and 7.4 respectively [13]. The authors also evaluated different chemical penetration enhancers. All the investigated enhancers, except propylene glycol (PG) (Q24: 51.90 mg; flux: 2.2 2 ± 0.15 mg/cm2/h), enhanced the permeation of ASPM across rat skin in the following increasing manner in comparison with phosphate buffer (Q24: 64.56 ± 4.55 mg; flux: 2.7 2 ± 0.20 mg cm2 h); PEG 400 (Q24: 80.19 ± 5.01 mg; flux: 3.2 2 ± 0.20 mg cm2 h); Tween 80 (Q24: 141.29 ± 7.24 mg; flux: 5.8 2 ± 0.31 mg/cm2/h); ethanol 10% (Q24: 151.90 ± 7.16 mg; flux: 6.1 3 ± 0.41 mg/cm2/h); DMSO (Q24: 161.29 ± 8.10 mg; flux: 6.50 ± 0.34 mg/cm2/h); ethanol 20% (Q24: 312.26 ± 16.66 mg/cm2; flux:12.5 1 ± 0.92 mg cm2 h) [13]. There is still considerable controversy regarding the ability of ultraflexible vesicles to cross intact stratum corneum [62]. What is less controversial is that the use of these vesicles may sometimes to lead to increased percutaneous diffusion [79]. In the specific case of ASPM, the objective of the research project was to increase ASPM bioavailability through the transdermal route by using combined strategy of chemical and nano-carrier (transfersomal) based approaches [13]. It has been postulated that the underlying mechanism of this flux enhancement is the hydration gradient [61].

1.17. Olanzapine Olanzapine (OLZ), chemically known as 2-methyl-4-(4-methyl1-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine, is used for the treatment of schizophrenia and other psychotic symptoms [80]. It has been documented in the literature that patients suffering from anxiety, depression, psychosis, and mania are noncompliant, and that transdermal drug delivery may be useful in facilitating patient compliance [81]. Recently, Aggarwal and coworkers used Eudragit©-based polymeric films to prepare olanzapine-loaded transdermal patches [81]. Span-20, anionic (sodium lauryl sulfate), cationic surfactant (benzalkonium chloride), and olive oil were used as sorption promoters. The transdermal film (area of 10 cm2) OD3 (span 20; 10%) exhibited the greatest cumulative amount of drug permeated

Table 1 Techniques for the percutaneous transport of selected psychotropic medications across animal and human skin models. Reference Method

Molecular Species

Skin Model(s)

[13] [81]

Asenapine Olanzapine

Rat skin Rat skin

Olanzapine Aripiprazole Chlorpromazine Chlorpromazine Haloperidol Haloperidol Haloperidol Haloperidol Haloperidol Risperidone Risperidone Risperidone Fluoxetine

Rat skin Human cadaver skin Porcine ear and human skin Pig skin Human, rabbit and hairless mouse skin Human skin Human skin Human and guinea pig skin Human epidermis Rat skin Rat skin Rabbit skin Hairless mouse skin, rat skin, and human cadaver skin w Human skin

[82] [84] [87] [88] [92] [93] [90] [91] [95] [103] [94] [101] [110] [112]

Nanotransfersomes Chemical penetration enhancers (span-20, sodium lauryl sulfate, benzalkonium chloride, olive oil) Skin permeation enhancers (corn oil, groundnut oil and jojoba oil) Penetration enhancers PLO gel Iontophoresis Permeation enhancer (1,8-cineole) Proniosomes Penetration enhancers Prodrugs (ethyl,propyl, butyl, octyl and decyl O-acyl esters of haloperidol) Cyclodextrins Penetration enhancers (olive oil and jojoba oil) Proniosomes Crystallization inhibitors Penetration enhancers (Azone™ [1-dodecyl-hexahydro-2H-azepin-2-one], SR-38 (4decyloxazolidin-2-one), and ethanol) Azone™, Transcutol™, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, Nmethyl pyrrolidone and lauric acid

Alprazolam

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(1.902 ± 0.021 mg/cm2) in 72 h. In addition, the magnitude of flux enhancement factor with nonionic surfactant (OD3) and olive oil (OE3) was 6.63 and 6.29 at 10% (w/w of polymer weight) concentration, respectively. This was significantly higher than with ionic surfactants (OB2 and OC3) and the control group (OA2) [81]. The same research laboratory also studied the influence of f corn (maize) oil, groundnut oil and jojoba oil on in vitro transport of olanzapine across rat skin [82]. Transdermal flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5 mg/ml concentration in a solvent system [82]. The interesting aspect of transdermal drug delivery research involving olanzapine is that effective management of schizophrenia patients is often compromised by patient non-adherence to pharmacotherapeutic regimen [82]. Noncompliance leads to relapse which results in hospitalization - the largest expenditure for this disease [82]. It is anticipated that a transdermal formulation will improve compliance and provide therapeutic concentration of the drug over a prolonged period of time. 1.18. Aripiprazole Aripiprazole (ARI) is an atypical neuroleptic which reduces positive and negative schizophrenia symptoms [83]. The drug is a partial agonist of D2 and D3 dopamine receptors and 5-HT1A serotonin receptors as well as an antagonist of 5-HT2A and 5-HT6 receptors [83]. Recently, the effect of vehicle systems, pH and enhancers on the transdermal delivery of aripiprazole (ARI) through human cadaver skin was investigated [84]. Gel formulations of 5% ARI were developed with 0.5% Carbopol 971P in quaternary vehicle systems consisting of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO)water and ethanol or isopropyl myristate (IPM) at a ratio of 40/40/5/15 [84]. The influence of pH of the gel formulations and fatty acids with different chain lengths on the percutaneous transport of ARI was examined. Transcutaneous flux of ARI from gel formulation with IPM and ethanol did not differ significantly. A four-fold enhancement in ARI flux was observed when the pH of the gel systems was reduced from pH 8.2 to pH 6 or pH 7 [84]. For fatty acids, the order of flux was lauric acid > myristic acid > caprylic acid > oleic acid. It is noteworthy that in all the cases, in vitro penetration rate of ARI across human cadaver skin followed zero order kinetics [84]. Most of the newly discovered active pharmaceutical ingredients (APIs) have poor water solubility, and the dissolution enhancement of the Biopharmaceutical Classification System (BCS) II type (poorly water-soluble, but highly permeable) drugs has become a significant pharmaceutical challenge [85]. Studying dissolution without permeability can be deceptive, since both of them can influence in vivo bioavailability [85]. From this standpoint, the investigation of the percutaneous penetration of human cadaver skin by ARI [84] is particularly significant as it sought to show that improved solubility through the use of different solvent systems could lead to permeation enhancement. 1.19. Chlorpromazine Chlorpromazine (CPZ) is a neuroleptic antipsychotic agent which acts by potently inhibiting dopamine D2 receptors [86]. However, the clinical benefit of CPZ is accompanied by several side effects, such as antiserotonergic activity and post-synaptic a1 adrenoceptor-blockade [86]. The feasibility of delivering CPZ transdermally has been investigated by numerous research laboratories [87,88]. The transcutaneous penetration of chlorpromazine hydrochloride from pluronic lecithin organogel (PLO gel) was recently studied [87]. The authors formulated PLO gels of chlorpromazine

hydrochloride by using isopropyl palmitate (IPP) or ricinoleic acid (RA) as the oil phase. In vitro transdermal delivery of chlorpromazine hydrochloride across porcine ear and human abdominal skin was evaluated [87]. The percutaneous transport of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. The theoretical steady state concentration of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were estimated to be 1.05, 1.20, and 1.50 ng/ml, respectively [87]. PLO gels only marginally increased the flux and the theoretical steady-state concentration of chlorpromazine. The required steady state concentration of chlorpromazine in human plasma is 100e300 ng/ml [87]. The authors calculated the target transdermal flux and concluded that the investigated PLO gels were not effective in delivering the required systemic levels of chlorpromazine [87].
Vicente Gonza
lez-Aramundiz also Alvarez-Figueroa and Jose investigated the in vitro iontophoretic transdermal delivery of chlorpromazine across porcine skin [88]. The authors demonstrated that anodal iontophoresis significantly enhanced the CPZ skin penetration and accumulation in comparison with passive controls [88]. In this set of experiments, the influence of drug concentration, sodium chloride content and current density was studied. Enhanced permeation of CPZ was observed with increased concentration while CPZ iontophoretic delivery was impeded by rising NaCl concentration [88]. Furthermore, when the current densities of 0.35 and 0.5 mA/cm2 were used for experiments, there was no statistically significant difference in the cumulative delivery of 0.5 mg/ml of CPZ (628.83 ± 203.46 versus 523.99 ± 207.24 mg/ cm2 respectively) [88]. The difficulty is delivering CPZ across the skin into systemic circulation is evident in the fact that pharmacists serving on hospice interdisciplinary teams have recommended the use of transdermal pluronic lecithin organogels (PLO gels) of chlorpromazine hydrochloride, despite the lack of any reliable clinical evidence supporting its transdermal use [87]. There are available enhancement techniques such as microneedles which can be studied in relation to the delivery of CPZ. The fact that the target flux was not achieved in the study by Asaab and coworkers [87] demonstrates the need to investigate other transdermal drug delivery techniques. 1.20. Haloperidol Haloperidol (HAL) is a neuroleptic agent used for the management of acute and chronic psychosis, schizophrenia, and delirium [89-91]. It has been suggested that the antipsychotic activity of haloperidol is attributable, at least partially, by its antagonism of the dopamine D2 receptor [89]. The daily oral dosages range from 0.5 mg (anxiety and agitation) to 30 mg (resistant schizophrenia) and the bioavailability is about 60% [92]. Using the Potts-Guy equation, a log P value of 4.3, molecular weight of 375.9 and an aqueous solubility of 14 mgmL
1, Elgorashi and coworkers predicted a maximum HP flux of 0.15 mg cm2 h from an aqueous vehicle [92]. Based on the rationale that low blood levels of 2e13 ngmL
1 are effective in the management of schizophrenia, the authors examined the feasibility of the transdermal delivery of this drug [92]. They used 10% 1,8-cineole as a chemical penetration enhancer for transcutaneous transport of HP across full-thickness human, rabbit and hairless mouse skin [92]. The permeability coefficient value (kp) from hypromellose was significantly facilitated by cineole by factors of 6.2, 5.6) and 3.0 for human, rabbit and mouse, respectively [92]. The authors sought to delineate the relative contributions of partition coefficient (K) and diffusion coefficient (D) in order to elucidate the mechanism of flux enhancement [92]. Using curve-fitting and the equation, kp ¼ (Kh)  (D/h2) where h is membrane thickness, it was shown that the enhancement ratios for

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K were 13.3 (8.3e20), 3.1 (2.5e3.9) and 2.0 (1.5e2.6). These were higher than those for D: 0.47 (0.41e0.55), 1.8 (1.6e2.1) and 1.5 (1.3e1.8) for full-thickness human, rabbit and hairless mouse skins respectively [92]. Mixtures of lipids and surfactants, known as proniosomes, have been used as carriers for drug delivery across the skin [93,94]. They have similar structure and properties to liposomes, but often have improved chemical stabilities due to the inclusion of surfactants in the formulation [93]. Azarbayjani and coworkers used proniosomes to enhance the transdermal delivery of HAL [93]. Span 40, Span 60, Span 85 and Tween 80 were used as surfactants to prepare the proniosomes. Cholesterol, lecithin and isopropyl alcohol were also included in the compositions of the drug delivery system. It was revealed that formulations with single surfactants increased the transdermal penetration of HAL more than formulations containing two surfactants [93]. There was a significant increase in the transdermal delivery of HAL from formulations containing surfactants with HLB value 16.7 with the HAL flux rate almost 2.8-fold higher than that of the control solution [93]. The number of carbons in the alkyl chain of the non-ionic surfactant correlated well with the in vitro permeation of HP though the epidermis. Furthermore, transcutaneous flux values were enhanced with increase in hydrophilicelipophilic balance (HLB) values of the surfactants [93]. Lim et al. recently studied the influence of terpenes, namely limonene, linalool and cineole, in propylene glycol on the percutaneous transport of HAL [90]. Relative to oxygenated linalool and cineole, hydrocarbon limonene was more effective as a chemical penetration enhancer; it increased human skin permeability and decreased lag time [90]. Limonene was subsequently used in an organogel formulation made from of the gelator dibutyllauroylglutamide and propylene glycol (PG) [90]. The time course of cumulative haloperidol (HAL) which penetrated across human abdominal skin with or without terpene is shown in Fig. 1. Morris and Heard also investigated the transdermal delivery of HAL prodrugs [91]. The authors studied the permeation of ethyl (HE), propyl (HP), butyl (HB), octyl (HO) and decyl (HD) O-acyl esters of haloperidol (HA) across full-thickness human and guinea pig skin [91]. The mean cumulative amounts of HE, HP and HB permeated through full-thickness fresh guinea pig skin [91] are shown in Fig. 2. The flux of HA was considerably greater than that of its derivatives and only the lowest molecular weight prodrug, HE,

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Fig. 2. Mean cumulative amount of HE, HP and HB permeated through full-thickness fresh guinea pig skin. Key: (A) HE; (-) HP; (:) HB; (e e) lactate formation (prodrugs: n ¼ 4, ±SEM; lactate formation: n ¼ 3, ±SEM) (reproduced with permission from reference [91]).

▵

permeated the skin to any appreciable extent [91]. The effect of cyclodextrins on transdermal permeation of HAL was also investigated [95]. It was shown that 0.01 M solution of randomly methylated b-cyclodextrin (RM b-CD) significantly increased the transdermal flux of HAL [95]. Interestingly, when the concentration of RM b-CD was increased to 0 M, there was lower drug penetration through the skin. The authors explained that this may be due to the supermolecular arrangements and concentration of RM b-CD which led to the formation of large aggregates which are too large to increase drug permeability [95]. Samanta et al. formulated and evaluated HAL-loaded matrixdiffusion type transdermal films by glass substrate technique using Eudragit® NE 30D, PVA and glycerin [96]. The authors studied percutaneous transport of HAL from this system across abdominal skin of albino rat. The authors carried out in vitro drug release study and the maximum release flux was found to be 7.38 mg/cm2/hr/2 for HAL fllms. The in vitro skin permeation studies through rat skin showed that the maximum permeation flux was 0.73 mg/cm2/hr [96]. Furthermore, the authors evaluated the tranquilizing efficacy of the films loaded with 10 mg of HAL (TPH2) by rotarod method with mice, and the minimum falling time was found to be 9 s at the 24th hr, compared to the control time of 300 s [96]. The sketch of a typical iontophoretic device is shown in Fig. 3. Electrosmosis and electrorepulsion are the major mechanisms in transdermal iontophoresis [41,97,98]. Since HAL is positively charged at physiological pH (7.4), it must be delivered from the anode [98]. Alvarez-Figueroa and coworkers investigated the transdermal iontophoretic transport pf HAL and showed that anodal iontophoresis significantly enhanced HAL skin penetration and accumulation in comparison with passive controls [98]. In addition, the authors demonstrated that iontophoretic transport of HAL increased with current density [98].

1.21. Risperidone

Fig. 1. Time course of cumulative haloperidol (HP) permeated through 0.785 cm2 of human abdominal skin with or without terpene. CHP ¼ 2.5 mg/mL, CTerp ¼ 5% v/v. Donor vehicle: PG-control (>); linalool/PG (,); limonene/PG ( ); cineole/PG (A) (reproduced with permission from reference [90]).

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Risperidone (RIS), 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]ethyl]-2-methyl- 4Hpyrid [1,2-a]pyrimidin-4-one, a benzisoxazole derivative, is an atypical antipsychotic medication which acts by targeting multiple neurotransmission receptors, particularly dopamine and serotonin (5-HT) receptors [99,100]. It is a dopamine (D2, D3) receptor antagonist, possessing

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Fig. 3. Iontophoresis using a Ag/AgCl electrode system. The anodal compartment contains an ionizable drug Dþ with its counter-ion A
and Na þ Cl
. Application of an electric potential causes a current to flow through the circuit (reproduced with permission from reference [41]).

antiserotonergic (5-HT2A, 5-HT2C), antiadregenic and antihistaminergic (H1) properties [100]. With oral formulations of antipsychotics, adherence to medication regimen is a common problem [101]. In addition, these dosage forms often show low bioavailability due to extensive first pass metabolism, risk of variable drug-plasma concentration due to sudden interruption and unpleasant extra-pyramidal adverse effects [102]. The feasibility of using the transdermal route for RIS delivery was recently investigated [103]. The authors designed transdermal patches using Eudragit® RL 100 and Eudragit® RS 100 as matrix forming polymers, as well as olive oil, groundnut oil and jojoba oil in different concentrations as enhancers [103]. Among the investigated systems, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, displayed the greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm2) in 72 h [103]. The effect of proniosomes on the transdermal delivery of risperidone has also been studied [94]. This pro-vesicular approach is based on the formation of ‘‘proniosomes’’ which are converted to niosomes following hydration [94]. The authors prepared proniosomes from cholesterol, Span 60 and the phospholipid G90. They used a four-factor three-level BoxeBehnken design to optimize formulation variables [94]. The optimum formulation was chosen based on the attainment of attaining the minimum vesicle size and the maximum % encapsulation efficiency and transdermal flux. Optimization was carried out by using the point prediction method [94]. The optimal formulation comprised of span 60 (90 mg), cholesterol (10 mg), phospholipid (90 mg), and risperidone (15 mg). This formulation led to a significantly higher skin permeation of the drug across rat skin in comparison with conventional liposomes [94]. The enhancement ratio (ER), encapsulation efficiency, vesicle size and transdermal flux values were 4.4, 90.43 1 ± 0.21%, 498.43 ± 1.27 nm and 117.42 8.61± mg.cm2.h respectively [94]. Weng and coworkers also developed a transdermal patch containing RIS and used different pressure sensitive adhesives (PSAs),

drug loading, and crystallization inhibitors to improve the formulation [101]. The skin penetration profiles of RIS from transdermal patches with different drug loading are shown in Fig. 4. The authors evaluated the percutaneous transport of RIS from 4 different acrylic PSAs with no functional group (Duro-Tak® 87e4098), hydroxyl group (Duro-Tak® 87e2287 and Duro-Tak® 87e2510), and carboxyl group (Duro-Tak® 87e2852) across excised rabbit skin [101]. To overcome high crystallization, several inhibitors such as polyvinylpolypyrrolidone (PVP), polyethylene glycol (PEG), surfactants and fatty acids were evaluated [101]. Furthermore, the authors increased the drug concentration in the pressure sensitive adhesive (PSA in order to facilitate percutaneous penetration across rabbit skin [101]. The cumulative amount of RIS delivered in 24 h from systems with different drug loading of 3%, 4%, 5%, 6% (w/w), were 108.06 ± 27.52, 180.30 ± 4.75, 285.54 ± 26.68, and 367.54 ± 14.56 mg/cm2 respectively [101]. In the study, the authors also showed the point to-point correlation between in vitro skin permeation rate and in vivo plasma concentration [101]. Recently, there has been a renewed interest in the use of ultradeformable vesicles for transdermal drug delivery [104]. Das and coworkers used transfersomal gel to deliver risperidone across excised porcine skin [102]. The transcutaneous flux of the optimized gel was 0.2387 ± 0.0245 mg/cm2/h [102]. The authors attributed the increased flux to hydration gradient [102]. According to the Cevc hypothesis, the most obvious natural transdermal gradient originates from water activity difference across the stratum corneum [65]. The transdermal hydration difference creates very strong force acting on the skin via vesicles which enforces widening of the weakest intercellular junctions in the barrier and creates 20-30-nm-wide transcutaneous channels [62,66].

1.22. Fluoxetine Fluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine) is selective serotonin reuptake inhibitor (SSRI), widely used for the management of a wide variety of

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Fig. 4. The skin penetration profiles of risperidone (RIS) from transdermal patches with different drug loadings (reproduced with permission from reference [101]).

Fig. 5. In vitro hairless mouse skin permeation profiles of FX from patches containing 20% (w/w) FX with no enhancers (C), 5% (w/w) IPM (B), 5% (w/w) Limonene (;), 5% (w/w) Oleic acid (△), 5% (w/w) Tween20 (-), and 5% (w/w) IPM þ 5% (w/w) Limonene (,) (reproduced with permission from reference [109]).

psychiatric disorders, including depression, bipolar disorder and anxiety disorders [105-109]. The drug is also utilized for the management of obesity, attention deficit hyperactivity disorder, bulimia, and panic disorder [110]. Fluoxetine (FX) increases serotonin levels in the synapse by inhibiting serotonin reuptake at the presynaptic neuron [108]. The drug is basic (pKa ¼ 9.4) and lipophilic (log P ¼ 4) [109]. It is commercially available only as oral formulations including tablets and capsules at doses of 10e60 mg/day [109]. Jung and coworkers recently postulated that transdermal drug delivery may be beneficial in reducing side effects associated with FX through decreased fluctuations in drug plasma concentration levels [109].

Fig. 6. In vitro hairless mouse skin permeation profiles of FX from PG solution containing FXB (0.5 w/v%) and IPM at concentrations of 0 (), 1 (B), 2 (;), and 5% (w/v) ( ) (n ¼ 3e6). (reproduced with permission from reference [108]).

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The authors developed fluoxetine-loaded drug-in adhesive (DIA) patch formulations from DuroTak 87e502B and investigated in vitro penetration of FX across hairless mouse, rat and human cadaver skins [109]. In vitro hairless mouse skin permeation profiles of FX from patches containing 20% (w/w) FX with different chemical penetration enhancers are shown in Fig. 5 [109]. The investigators showed that Cmax of FX after the transdermal administration of the formulation in rats was 52.38 ng/ml, and plasma concentration of FX was maintained for 36 h. More importantly, the predicted human steady state concentration, Css (55.79 ng/ml) and Cmax (27.35 ng/ml) were in good agreement with the reported plasma levels (15e55 ng/ml) of oral FX formulations [109]. The same research group also carried out another study with penetration enhancers [108]. In vitro hairless mouse skin permeation

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profiles of FX from PG solution containing FXB (0.5 w/v%) and different concentrations of IPM are shown in Fig. 6 [108]. The authors also demonstrated that the use of isopropyl myristate and isopropyl myristate (IPM)elimonene mixture in transdermal formulations led to mean FX steady-state plasma concentrations (Css) of 66.20 or 77.55 ng/mL, respectively following administration in rats [108]. The concentration profile was maintained over 36 h and had a good correlation with the predicted Css from the in vitro data [108]. Taken together, these data suggest that it may be feasible to develop clinically relevant FX formulations. Parikh and Gosh also investigated the influence of chemical penetration enhancers such as Azone™ (1-dodecyl-hexahydro-2Hazepin-2-one), SR-38 (4-decyloxazolidin-2-one), and ethanol on the percutaneous transport of fluoxetine hydrochloride (permeation of FX.HCl increased by 6 times when 2% Azone™ was used and by about 8 times when 5% wt/vol SR-38 was used [110]. The authors also evaluated the effect of microemulsion on transdermal delivery of FX.HCl. Ethanol at 65% v/v was shown to increase the permeation of fluoxetine the most while microemulsion decreased the transcutaneous flux of FX [110]. When 65% of ethanol was used as the penetration enhancer, the flux value was 79.71 ± 10.80 mg/ cm2/hr. Transdermal permeation of FX.HCl increased by 6 times when 2% Azone™ was used and by about 8 times when 5% wt/vol SR-38 was used [110]. 1.23. Alprazolam From a chemical standpoint, alprazolam (ALP) is 8-chloro-1methyl-6-phenyl-4H-[1,2,4]triazolo[4,3,-] [1,4]benzodiazepine [111]. The drug binds nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects muscle relaxation, anticonvulsant activity, motor coordination, and memory [111]. ALP is used for the management of panic disorder [12]. Recently, Soler et al. formulated monolithic drug in adhesive matrix using acrylic pressure-sensitive adhesives (PSA) of acrylate vinyl acetate (Duro-tack®) and then investigated the influence of permeation enhancers as Azone™, Transcutol™, propylene glycol, dodecyl alcohol, decyl alcohol, diethanolamine, N-methyl pyrrolidone and lauric acid on the transdermal delivery of ALP [112]. The authors showed that a combination of permeation enhancers from different chemical groups increased transdermal ALP flux by 33 fold compared to an aqueous saturated dispersion (from 0.054 ± 0.019 to 1.76 ± 0.21 mg h cm
2) [112]. 1.24. Transdermal drug delivery systems loaded with psychotropic medications and approved for clinical use Two psychotropic medications have been approved by the Food and Drug Administration as transdermal patches. These are Daytrana® (methylphenidate) [113] and Emsam® (selegiline) [114]. Dthreo-methylphenidate hydrochloride (D-threo-MPH) is the pharmacologically active D-threo enantiomer of racemic MPH [115]. It has been suggested that L-threo-methylphenidate hydrochloride (L-threo-MPH) does not seem to contribute to the clinical efficacy of D,L-threo-MPH [115]. Daytrana® is the only patch prescribed for attention deficit hyperactivity disorder (ADHD) in children [116]. A surveillance of Daytana® indicated that youth exclusively using the medication appear to have lower rates of misuse and diversion compared to users of other prescription stimulants for ADHD [116]. Nevertheless, it is important to note that the National Monitoring of Adolescent Prescription Stimulants Study found some misuse and diversion of Daytrana [116]. In addition, chemical leukoderma (chemically induced acquired hypopigmented dermatosis) has also reportedly been induced by transdermal methylphenidate patch [117]. Unfortunately, the effect of

psychostimulants such as MPH on catecholamine efflux leads to drug abuse [118]. Improving clinical efficacy for catecholaminergic drugs and reducing abuse liability has led to the introduction of once-daily formulations and novel drug-delivery systems [118]. Despite these adverse events, clinical trials have shown that approximately 70% of individuals with ADHD will respond to psychostimulant medications, i.e. those containing amphetamine or MPH while the response rates to the non-stimulant, atomoxetine, are 50e60% [118]. Emsam® is the first transdermal patch approved for major depressive disorder [119]. The transdermal drug delivery system recently approved by the FDA provides greater systemic delivery of selegiline to the brain with the relative sparing of gastrointestinal MAO-A enzyme [120]. However, transdermal patches have limitations resulting from cosmetic concerns, adhesion to the skin, the dependence of absorption on skin thickness, degradation issues as a result of patch exposure to heat or water as well as individual skin reactions [119]. Despite these shortcomings, prolonged, 24-h selegiline delivery from Emsam® might help patients adhere to treatment regimen, which can reduce the incidence of recurrence and the relapse of MDD [119]. 2. Conclusions Only a few transdermal patches have been approved for the management of psychiatric disorders despite the issues of noncompliance and low bioavailability that are well known for this group of therapeutic agents. There has been a widespread interest in the use of different enhancement strategies (prodrugs, chemical penetration enhancers, and proniosomes) to increase the transdermal delivery of psychotropic medications. A potential exists to extend other popular enhancement techniques such as sonophoresis and microneedles to psychotropic agents. Another important aspect of transdermal drug delivery research in this area is to address issues of irritation and safety. In this review, the application of several transdermal drug delivery techniques to psychotropic medications is discussed and the benefits of these drug delivery systems have also been highlighted. Although more research needs to be done in this area, significant achievements have already been recorded with the FDA approval of Daytrana® and Emsam®. References [1] H.A. Whiteford, A.J. Ferrari, L. Degenhardt, V. Feigin, T. Vos, Global burden of mental, neurological, and substance use disorders: an analysis from the global burden of disease study 2010, in: V. Patel, et al. (Eds.), Mental, Neurological, and Substance Use Disorders: Disease Control Priorities, Third Edition, vol. 4, International Bank for Reconstruction and Development/The World Bank, Washington, DC, 2016, p. 2016. [2] S. Alkhadhari, A.O. Alsabbrri, I.H. Mohammad, A.A. Atwan, F. Alqudaihi, M.A. Zahid, Prevalence of psychiatric morbidity in the primary health clinic attendees in Kuwait, J. Affect Disord. 195 (2016) 15e20. [3] H.A. Whiteford, A.J. Ferrari, L. Degenhardt, V. Feigin, T. Vos, The global burden of mental, neurological and substance use disorders: an analysis from the global burden of disease study 2010, PLoS One 10 (2) (2015) e0116820. [4] R.N. Lipari, S.L. Hedden, A. Hughes, Substance use and mental health estimates from the 2013 national survey on drug use and health: overview of findings, in: The CBHSQ Report, 2013. Rockville MD. [5] F. Schürhoff, G. Fond, F. Berna, E. Bulzacka, J. Vilain, D. Capdevielle, D. Misdrahi, M. Leboyer, P.M. Llorca, A National network of schizophrenia expert centres: an innovative tool to bridge the research-practice gap, Eur. Psychiatry 30 (6) (2015) 728e735. [6] R.B. Rocha, E.R. Dondossola, A.J. Grande, T. Colonetti, L.B. Ceretta, I.C. Passos, J. Quevedo, M.I. da Rosa, Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: a meta-analysis study, J. Psychiatr. Res. 83 (2016) 47e53. [7] V. Vilgis, J. Chen, T.J. Silk, R. Cunnington, A. Vance, Frontoparietal function in young people with dysthymic disorder (DSM-5: persistent depressive disorder) during spatial working memory, J. Affect. Disord. 160 (2014) 34e42. [8] N. Laurin, A. Ickowicz, T. Pathare, M. Malone, R. Tannock, R. Schachar, J.L. Kennedy, C.L. Barr, Investigation of the G protein subunit Gaolf gene

K. Ita / Journal of Drug Delivery Science and Technology 39 (2017) 247e259

[9]

[10]

[11]

[12]

[13]

[14] [15]

[16]

[17]

[18]

[19] [20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29] [30]

[31]

[32]

[33]

(GNAL) in attention deficit/hyperactivity disorder, J. Psychiatr. Res. 42 (2) (2008) 117e124. B.J. Hasselbalch, U. Knorr, L.V. Kessing, Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review, J. Affect. Disord. 134 (1e3) (2011) 20e31. J.M. Gatt, K.L.O. Burton, L.M. Williams, P.R. Schofield, Specific and common genes implicated across major mental disorders: a review of meta-analysis studies, J. Psychiatr. Res. 60 (2015) 1e13. C.H. Wong, Z.U.B. Sultan Shah, C.L. Teng, T.Q. Lin, Z.A. Majeed, C.W. Chan, A systematic review of anxiety prevalence in adults within primary care and community settings in Malaysia, Asian J. Psychiatry 24 (2016) 110e117. L.A. Batista, A.S. Haibara, L.C. Schenberg, F.A. Moreira, Effects of alprazolam and cannabinoid-related compounds in an animal model of panic attack, Behav. Brain Res. 317 (2017) 508e514. A.B. Shreya, R.S. Managuli, J. Menon, L. Kondapalli, A.R. Hegde, K. Avadhani, P.K. Shetty, M. Amirthalingam, G. Kalthur, S. Mutalik, Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations, J. Liposome Res. 26 (3) (2016) 221e232. S.C. Stoner, H.A. Pace, Asenapine: a clinical review of a second-generation antipsychotic, Clin. Ther. 34 (5) (2012) 1023e1040. H. Shin, J.-H. Song, Antipsychotics, chlorpromazine and haloperidol inhibit voltage-gated proton currents in BV2 microglial cells, Eur. J. Pharmacol. 738 (2014) 256e262. Y.-J. Yang, J.-W. Xiong, Y. Zhao, J.-Q. Zhan, H.-B. Chen, K. Yan, M.-R. Hu, B. Yu, B. Wei, Increased plasma asymmetric dimethylarginine is associated with cognitive deficits in patients with schizophrenia, Psychiatry Res. 246 (2016) 480e484. G. Venkatasubramanian, M. Debnath, The TRIPS (Toll-like receptors in immuno-inflammatory pathogenesis) hypothesis: a novel postulate to understand schizophrenia, Prog. Psychopharmacol. Biol. Psychiatry 44 (2013) 301e311. M. Koga, A.V. Serritella, A. Sawa, T.W. Sedlak, Implications for reactive oxygen species in schizophrenia pathogenesis, Schizophrenia Res. 176 (1) (2016) 52e71. J. Zhang, X.-y. Sun, L.-y. Zhang, MicroRNA-7/Shank3 axis involved in schizophrenia pathogenesis, J. Clin. Neurosci. 22 (8) (2015) 1254e1257. Y.-X. Huo, L. Huang, D.-F. Zhang, Y.-G. Yao, Y.-R. Fang, C. Zhang, X.-J. Luo, Identification of SLC25A37 as a major depressive disorder risk gene, J. Psychiatr. Res. 83 (2016) 168e175. L.B. Bergantin, A. Caricati-Neto, Challenges for the pharmacological treatment of neurological and psychiatric disorders: implications of the Ca2þ/ cAMP intracellular signalling interaction, Eur. J. Pharmacol. 788 (2016) 255e260. L. Gong, Y. Yin, C. He, Q. Ye, F. Bai, Y. Yuan, H. Zhang, L. Lv, H. Zhang, C. Xie, Z. Zhang, Disrupted reward circuits is associated with cognitive deficits and depression severity in major depressive disorder, J. Psychiatr. Res. 84 (2017) 9e17. A.V. Ravindran, C. Cameron, R. Bhatla, L.N. Ravindran, T.L. da Silva, Paroxetine in the treatment of dysthymic disorder without co-morbidities: a doubleblind, placebo-controlled, flexible-dose study, Asian J. Psychiatry 6 (2) (2013) 157e161. R.L. Levin, J.S. Rawana, Attention-deficit/hyperactivity disorder and eating disorders across the lifespan: a systematic review of the literature, Clin. Psychol. Rev. 50 (2016) 22e36. N. Rommelse, M. van der Kruijs, J. Damhuis, I. Hoek, S. Smeets, K.M. Antshel, L. Hoogeveen, S.V. Faraone, An evidenced-based perspective on the validity of attention-deficit/hyperactivity disorder in the context of high intelligence, Neurosci. Biobehav. Rev. 71 (2016) 21e47. S.-Y. Oh, Y.-K. Kim, Association of norepinephrine transporter gene polymorphisms in attention-deficit/hyperactivity disorder in Korean population, Prog. Psychopharmacol. Biol. Psychiatry 73 (2017) 56e63. N. Hoertel, C. Blanco, H. Peyre, M.M. Wall, K. McMahon, P. Gorwood, C. Lemogne, F. Limosin, Differences in symptom expression between unipolar and bipolar spectrum depression: results from a nationally representative sample using item response theory (IRT), J. Affect. Disord. 204 (2016) 24e31. C. Blanco, W.M. Compton, T.D. Saha, B.I. Goldstein, W.J. Ruan, B. Huang, B.F. Grant, Epidemiology of DSM-5 bipolar I disorder: results from the national epidemiologic survey on alcohol and related conditions e III, J. Psychiatr. Res. 84 (2017) 310e317. D.W. Grupe, Chapter 26-decision-making in anxiety and its disorders, in: Decision Neuroscience, Academic Press, San Diego, 2017, pp. 327e338. C. Kawashima, Y. Tanaka, A. Inoue, M. Nakanishi, K. Okamoto, Y. Maruyama, H. Oshita, Y. Ishitobi, S. Aizawa, K. Masuda, H. Higuma, M. Kanehisa, T. Ninomiya, J. Akiyoshi, Hyperfunction of left lateral prefrontal cortex and automatic thoughts in social anxiety disorder: a near-infrared spectroscopy study, J. Affect. Disord. 206 (2016) 256e260. Z. Zou, Y. Huang, J. Wang, Y. He, W. Min, X. Chen, J. Wang, B. Zhou, Association of childhood trauma and panic symptom severity in panic disorder: exploring the mediating role of alexithymia, J. Affect. Disord. 206 (2016) 133e139. J.R. Stevens, M. Justin Coffey, M. Fojtik, K. Kurtz, T.A. Stern, The use of transdermal therapeutic systems in psychiatric care: a primer on patches, Psychosomatics 56 (5) (2015) 423e444. J. Li, W. Xu, Y. Liang, H. Wang, The Application of Skin Metabolomics in the

257

Context of Transdermal Drug Delivery. (Pharmacological Reports). [34] B. Lynch, S. Bancelin, C. Bonod-Bidaud, J.B. Gueusquin, F. Ruggiero, M.C. Schanne-Klein, J.M. Allain, A novel microstructural interpretation for the biomechanics of mouse skin derived from multiscale characterization, Acta Biomater. 50 (2017) 302e311. [35] G.K. Menon, G.W. Cleary, M.E. Lane, The structure and function of the stratum corneum, Int. J. Pharm. 435 (1) (2012) 3e9. [36] A.G. Doukas, N. Kollias, Transdermal drug delivery with a pressure wave, Adv. Drug Deliv. Rev. 56 (5) (2004) 559e579. [37] H.J. Hirschberg, E. van Riet, D. Oosterhoff, J.A. Bouwstra, G.F. Kersten, Animal models for cutaneous vaccine delivery, Eur. J. Pharm. Sci. 71 (2015) 112e122. [38] V.R. Sherman, Y. Tang, S. Zhao, W. Yang and M.A. Meyers, Structural characterization and viscoelastic constitutive modeling of skin. Acta Biomater. http://dx.doi.org/10.1016/j.actbio.2017.02.011. [Epub ahead of print] [39] B.W. Barry, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur. J. Pharm. Sci. 14 (2) (2001) 101e114. [40] M.B. Delgado-Charro, R.H. Guy, Effective use of transdermal drug delivery in children, Adv. Drug Deliv. Rev. 73 (0) (2014) 63e82. [41] Y.N. Kalia, A. Naik, J. Garrison, R.H. Guy, Iontophoretic drug delivery, Adv. Drug Deliv. Rev. 56 (5) (2004) 619e658. [42] K. Malinovskaja-Gomez, H.I. Labouta, M. Schneider, J. Hirvonen, T. Laaksonen, Transdermal iontophoresis of flufenamic acid loaded PLGA nanoparticles, Eur. J. Pharm. Sci. 89 (2016) 154e162. [43] K. Ita, Dermal/transdermal delivery of small interfering RNA and antisense oligonucleotides- advances and hurdles, Biomed. Pharmacother. 87 (2017) 311e320. [44] J. Manikkath, A.R. Hegde, G. Kalthur, H.S. Parekh, S. Mutalik, Influence of peptide dendrimers and sonophoresis on the transdermal delivery of ketoprofen, Int. J. Pharm. 521 (1e2) (2017) 110e119. [45] L. Yin, F.H. Qin, Y. Zhou, X. Qi, Enhancing percutaneous permeability of sinomenine hydrochloride using dual-frequency sonophoresis, J. Drug Deliv. Sci. Technol. 36 (2016) 62e67. [46] Y. Cao, Y. Tao, Y. Zhou, S. Gui, Development of sinomenine hydrochlorideloaded polyvinylalcohol/maltose microneedle for transdermal delivery, J. Drug Deliv. Sci. Technol. 35 (2016) 1e7. [47] M.A. Lesniewska-Kowiel, I. Muszalska, Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds, Eur. J. Med. Chem. 129 (2017) 53e71. [48] K.B. Ita, Prodrugs for transdermal drug delivery - trends and challenges, J. Drug Target 24 (8) (2016) 671e678. [49] H. Devarajan-Ketha, K.B. Sloan, N,N'-dialkylaminoalkylcarbonyl (DAAC) prodrugs and aminoalkylcarbonyl (AAC) prodrugs of 4-hydroxyacetanilide and naltrexone with improved skin permeation properties, Bioorg Med. Chem. Lett. 21 (13) (2011) 4078e4082. [50] X. Liu, P. Quan, S. Li, C. Liu, Y. Zhao, Y. Zhao, L. Fang, Time dependence of the enhancement effect of chemical enhancers: molecular mechanisms of enhancing kinetics, J. Control Release 248 (2017) 33e44. [51] K.B. Ita, Chemical penetration enhancers for transdermal drug delivery success and challenges, Curr. Drug Deliv. 12 (6) (2015) 645e651. [52] D. Mohammed, K. Hirata, J. Hadgraft, M.E. Lane, Influence of skin penetration enhancers on skin barrier function and skin protease activity, Eur. J. Pharm. Sci. 51 (2014) 118e122. [53] A.C. Williams, B.W. Barry, Penetration enhancers, Adv. Drug Deliv. Rev. 64 (Supplement) (2012) 128e137. [54] V. Cizinauskas, N. Elie, A. Brunelle, V. Briedis, Fatty acids penetration into human skin ex vivo: a TOF-SIMS analysis approach, Biointerphases 12 (1) (2017) 011003. [55] S. Ghanbarzadeh, A. Khorrami, S. Arami, Nonionic surfactant-based vesicular system for transdermal drug delivery, Drug Deliv. 22 (8) (2015) 1071e1077. [56] P. Arunothayanun, M.S. Bernard, D.Q. Craig, I.F. Uchegbu, A.T. Florence, The effect of processing variables on the physical characteristics of non-ionic surfactant vesicles (niosomes) formed from a hexadecyl diglycerol ether, Int. J. Pharm. 201 (1) (2000) 7e14. [57] A. Sosnik, A.M. Carcaboso, R.J. Glisoni, M.A. Moretton, D.A. Chiappetta, New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery, Adv. Drug Deliv. Rev. 62 (4e5) (2010) 547e559. [58] H. Liu, L. Tu, Y. Zhou, Z. Dang, L. Wang, J. Du, J. Feng, K. Hu, Improved bioavailability and antitumor effect of docetaxel by TPGS modified proniosomes: in vitro and in vivo evaluations, Sci. Rep. 7 (2017) 43372. [59] G.S. Chin, H. Todo, W.R. Kadhum, M.A. Hamid, K. Sugibayashi, In vitro permeation and skin retention of alpha-mangostin proniosome, Chem. Pharm. Bull. (Tokyo) 64 (12) (2016) 1666e1673. [60] M. Ravaghi, C. Sinico, S.H. Razavi, S.M. Mousavi, E. Pini, A.M. Fadda, Proniosomal powders of natural canthaxanthin: preparation and characterization, Food Chem. 220 (2017) 233e241. [61] G. Cevc, Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery, Crit. Rev. Ther. Drug Carr. Syst. 13 (3e4) (1996) 257e388. [62] K. Ita, Current status of ethosomes and elastic liposomes in dermal and transdermal drug delivery, Curr. Pharm. Des. 22 (33) (2016 Nov 18) 5120e5126. €tzlein, G. Blume, Ultraflexible vesicles, [63] G. Cevc, D. Gebauer, J. Stieber, A. Scha Transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin, Biochimica Biophysica Acta (BBA) - Biomembr. 1368 (2) (1998) 201e215.

258

K. Ita / Journal of Drug Delivery Science and Technology 39 (2017) 247e259

[64] A. Ahad, A.A. Al-Saleh, A.M. Al-Mohizea, F.I. Al-Jenoobi, M. Raish, A.E. Yassin, M.A. Alam, Pharmacodynamic study of eprosartan mesylate-loaded transfersomes carbopol(R) gel under dermaroller(R) on rats with methyl prednisolone acetate-induced hypertension, Biomed. Pharmacother. 89 (2017) 177e184. [65] G. Cevc, D. Gebauer, Hydration-driven transport of deformable lipid vesicles through fine pores and the skin barrier, Biophys. J. 84 (2 Pt 1) (2003) 1010e1024. [66] G. Cevc, A. Schatzlein, H. Richardsen, Ultradeformable lipid vesicles can penetrate the skin and other semi-permeable barriers unfragmented. Evidence from double label CLSM experiments and direct size measurements, Biochim. Biophys. Acta 1564 (1) (2002) 21e30. €tzlein, D. Gebauer, A. Paul, The skin: a pathway for [67] G. Cevc, G. Blume, A. Scha systemic treatment with patches and lipid-based agent carriers, Adv. Drug Deliv. Rev. 18 (3) (1996) 349e378. [68] D. Marro, Y.N. Kalia, M.B. Delgado-Charro, R.H. Guy, Contributions of electromigration and electroosmosis to iontophoretic drug delivery, Pharm. Res. 18 (12) (2001) 1701e1708. [69] A. Sieg, R.H. Guy, M.B. Delgado-Charro, Electroosmosis in transdermal iontophoresis: implications for noninvasive and calibration-free glucose monitoring, Biophys. J. 87 (5) (2004) 3344e3350. [70] K. Ita, Transdermal iontophoretic drug delivery: advances and challenges, J. Drug Target (2015) 1e6. [71] G. Ma, C. Wu, Microneedle, bio-microneedle and bio-inspired microneedle: a review, J. Control Release 251 (2017) 11e23. [72] M.T. Hoang, K.B. Ita, D.A. Bair, Solid microneedles for transdermal delivery of amantadine hydrochloride and pramipexole dihydrochloride, Pharmaceutics 7 (4) (2015) 379e396. [73] Y. Deng, J. Chen, Y. Zhao, X. Yan, L. Zhang, K. Choy, J. Hu, H.J. Sant, B.K. Gale, T. Tang, Transdermal delivery of siRNA through microneedle array, Sci. Rep. 6 (2016) 21422. [74] G. Cole, J. McCaffrey, A.A. Ali, J.W. McBride, C.M. McCrudden, E.M. VincentePerez, R.F. Donnelly, H.O. McCarthy, Dissolving microneedles for DNA vaccination: improving functionality via polymer characterization and RALA complexation, Hum. Vaccin Immunother. 13 (1) (2017) 50e62. [75] M.A. Boks, W.W. Unger, S. Engels, M. Ambrosini, Y. Kooyk, R. Luttge, Controlled release of a model vaccine by nanoporous ceramic microneedle arrays, Int. J. Pharm. 491 (1e2) (2015) 375e383. [76] M. Isaac, C. Holvey, Transdermal patches: the emerging mode of drug delivery system in psychiatry, Ther. Adv. Psychopharmacol. 2 (6) (2012) 255e263. [77] P. Ghasri, S. Gattu, N. Saedi, A.K. Ganesan, Chemical leukoderma after the application of a transdermal methylphenidate patch, J. Am. Acad. Dermatol (2012) e237ee238. United States. [78] K.C. Lee, J.J. Chen, Transdermal selegiline for the treatment of major depressive disorder, Neuropsychiatr. Dis. Treat. 3 (5) (2007) 527e537. [79] J.H. Choi, S.H. Cho, J.J. Yun, Y.B. Yu, C.W. Cho, Ethosomes and transfersomes for topical delivery of ginsenoside rhl from red ginseng: characterization and in vitro evaluation, J. Nanosci. Nanotechnol. 15 (8) (2015) 5660e5662. [80] S.G. Musharraf, M. Ameer, A. Ali, MALDI-MS analysis and theoretical evaluation of olanzapine as a UV laser desorption ionization (LDI) matrix, J. Pharm. Biomed. Anal. 132 (2017) 190e194. [81] G. Aggarwal, S. Dhawan, S.L. Harikumar, Formulation, in vitro, and in vivo evaluation of matrix-type transdermal patches containing olanzapine, Pharm. Dev. Technol. 18 (4) (2013) 916e925. [82] G. Aggarwal, S. Dhawan, S.L. HariKumar, Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation, Curr. Drug Deliv. 9 (2) (2012) 172e181. [83] P. Ratajczak, K. Kus, K. Gołembiowska, K. Noworyta-Sokołowska, A. Wo
zniak, T. Zaprutko, E. Nowakowska, The influence of aripiprazole and olanzapine on neurotransmitters level in frontal cortex of prenatally stressed rats, Environ. Toxicol. Pharmacol. 46 (2016) 122e130. [84] M.A. Hossain, S.U. Ahmed, F.M. Plakogiannis, Effect of vehicle systems, pH and enhancers on the permeation of highly lipophilic aripiprazole from Carbopol 971P gel systems across human cadaver skin, Drug Dev. Ind. Pharm. 38 (3) (2012) 323e330.
Kiserdei, T. Vigh, B. Sinko
, A. Marosi, [85] E. Borb
as, A. Balogh, K. Bocz, J. Müller, E.
sz, Z. Doh
A. Hala anyos, L. Szente, G.T. Balogh, Z.K. Nagy, In vitro dissolutionepermeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using mFlux™, Int. J. Pharm. 491 (1e2) (2015) 180e189. [86] H.-J. Li, Y.-J. Zhang, L. Zhou, F. Han, M.-Y. Wang, M.-Q. Xue, Z. Qi, Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel, Eur. J. Pharmacol. 735 (2014) 38e43. [87] H. Alsaab, R.M. Alzhrani, S.H. Boddu, Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin, Drug Dev. Ind. Pharm. 42 (8) (2016) 1258e1266. [88] M.J. Alvarez-Figueroa, J.V. Gonzalez-Aramundiz, Passive and iontophoretic transdermal penetration of chlorpromazine, Pharm. Dev. Technol. 13 (4) (2008) 271e275. [89] Y. Shinoda, H. Tagashira, M.S. Bhuiyan, H. Hasegawa, H. Kanai, K. Fukunaga, Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction, J. Pharmacol. Sci. 131 (3) (2016) 172e183. [90] P.F. Lim, X.Y. Liu, L. Kang, P.C. Ho, Y.W. Chan, S.Y. Chan, Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol, Int. J. Pharm.

311 (1e2) (2006) 157e164. [91] A.P. Morris, K.R. Brain, C.M. Heard, Skin permeation and ex vivo skin metabolism of O-acyl haloperidol ester prodrugs, Int. J. Pharm. 367 (1e2) (2009) 44e50. [92] A.S. Elgorashi, C.M. Heard, E.M. Niazy, O.H. Noureldin, W.J. Pugh, Transdermal delivery enhancement of haloperidol from gel formulations by 1,8cineole, J. Pharm. Pharmacol. 60 (6) (2008) 689e692. [93] A.F. Azarbayjani, E.H. Tan, Y.W. Chan, S.Y. Chan, Transdermal delivery of haloperidol by proniosomal formulations with non-ionic surfactants, Biol. Pharm. Bull. 32 (8) (2009) 1453e1458. [94] S.S. Imam, M. Aqil, M. Akhtar, Y. Sultana, A. Ali, Formulation by design-based proniosome for accentuated transdermal delivery of risperidone: in vitro characterization and in vivo pharmacokinetic study, Drug Deliv. 22 (8) (2015) 1059e1070. [95] A.F. Azarbayjani, H. Lin, C.W. Yap, Y.W. Chan, S.Y. Chan, Surface tension and wettability in transdermal delivery: a study on the in-vitro permeation of haloperidol with cyclodextrin across human epidermis, J. Pharm. Pharmacol. 62 (6) (2010) 770e778. [96] M.K. Samanta, R. Dube, B. Suresh, Transdermal drug delivery system of haloperidol to overcome self-induced extrapyramidal syndrome, Drug Dev. Ind. Pharm. 29 (4) (2003) 405e415. [97] R.H. Guy, Y.N. Kalia, M.B. Delgado-Charro, V. Merino, A. Lopez, D. Marro, Iontophoresis: electrorepulsion and electroosmosis, J. Control Release 64 (1e3) (2000) 129e132. [98] M.J. Alvarez-Figueroa, I. Araya-Silva, C. Diaz-Tobar, Iontophoretic transdermal delivery of haloperidol, Pharm. Dev. Technol. 11 (3) (2006) 371e375. [99] J. Lian, B. Pan, C. Deng, Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats, Pharmacol. Rep. 68 (5) (2016) 1028e1035. [100] K.P. Singh, M.K. Singh, M. Singh, Effects of prenatal exposure to antipsychotic risperidone on developmental neurotoxicity, apoptotic neurodegeneration and neurobehavioral sequelae in rat offspring, Int. J. Dev. Neurosci. 52 (2016) 13e23. [101] W. Weng, P. Quan, C. Liu, H. Zhao, L. Fang, Design of a drug-in-adhesive transdermal patch for risperidone: effect of drug-additive interactions on the crystallization inhibition and in vitro/in vivo correlation study, J. Pharm. Sci. 105 (10) (2016) 3153e3161. [102] B. Das, S.O. Sen, R. Maji, A.K. Nayak, K.K. Sen, Transferosomal gel for transdermal delivery of risperidone: formulation optimization and ex vivo permeation, J. Drug Deliv. Sci. Technol. 38 (2017) 59e71. [103] G. Aggarwal, S. Dhawan, S.L. Hari Kumar, Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone, Drug Dev. Ind. Pharm. 39 (1) (2013) 39e50. [104] J. Brewer, M. Bloksgaard, J. Kubiak, J.A. Sorensen, L.A. Bagatolli, Spatially resolved two-color diffusion measurements in human skin applied to transdermal liposome penetration, J. Invest. Dermatol 133 (5) (2013) 1260e1268. [105] H. Shan, Y. Bian, Z. Shu, L. Zhang, J. Zhu, J. Ding, M. Lu, M. Xiao, G. Hu, Fluoxetine protects against IL-1b-induced neuronal apoptosis via downregulation of p53, Neuropharmacology 107 (2016) 68e78. [106] M.A. Tantawy, N.Y. Hassan, N.A. Elragehy, M. Abdelkawy, Simultaneous determination of olanzapine and fluoxetine hydrochloride in capsules by spectrophotometry, TLC-spectrodensitometry and HPLC, J. Adv. Res. 4 (2) (2013) 173e180. [107] J.Y. Lee, H.Y. Choi, T.Y. Yune, Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury, Neuropharmacology 109 (2016) 78e87. [108] E. Jung, Y.P. Kang, I.S. Yoon, J.S. Kim, S.W. Kwon, S.J. Chung, C.K. Shim, D.D. Kim, Effect of permeation enhancers on transdermal delivery of fluoxetine: in vitro and in vivo evaluation, Int. J. Pharm. 456 (2) (2013) 362e369. [109] E. Jung, E.Y. Lee, H.K. Choi, S.J. Ban, S.H. Choi, J.S. Kim, I.S. Yoon, D.D. Kim, Development of drug-in-adhesive patch formulations for transdermal delivery of fluoxetine: in vitro and in vivo evaluations, Int. J. Pharm. 487 (1e2) (2015) 49e55. [110] D.K. Parikh, T.K. Ghosh, Feasibility of transdermal delivery of fluoxetine, AAPS Pharm. Sci. Tech. 6 (2) (2005) E144eE149. [111] U.K. Chhalotiya, N.M. Patel, D.A. Shah, F.A. Mehta, K.K. Bhatt, Thin-layer chromatography method for the simultaneous quantification and stability testing of alprazolam and mebeverine in their combined pharmaceutical dosage form, J. Taibah Univ. Sci. 11 (2017) 66e75. [112] L.I. Soler, A. Boix, J. Lauroba, H. Colom, J. Domenech, Transdermal delivery of alprazolam from a monolithic patch: formulation based on in vitro characterization, Drug Dev. Ind. Pharm. 38 (10) (2012) 1171e1178. [113] M. Mayhew, Drugs for attention deficit hyperactivity disorder, J. Nurse Pract. 3 (1) (2007) 50e52. [114] P.J. Horn, I. Reti, G. Jayaram, Transdermal selegiline in patients receiving electroconvulsive therapy, Psychosomatics 51 (2) (2010) 176e178. [115] C. Zhang, H. Luo, G. Lin, Z. Zhu, F. Zhang, J. Zhang, Y. Wu, J. Luo, H. Wang, Transdermal patches for D-threo-methylphenidate (free base): formulation aspects and in vivo pharmacokinetics, J. Drug Deliv. Sci. Technol. 35 (2016) 50e57. [116] C. Delcher, C.W. Striley, S. Bradford, S.H. Schnoll, M.A. Sembower, L.B. Cottler, 11. Use, misuse and diversion of the methylphenidate transdermal system: results from the national monitoring of adolescent prescription stimulants study (N-MAPSS), J. Adolesc. Health 52 (2, Supplement 1) (2013) S20.

K. Ita / Journal of Drug Delivery Science and Technology 39 (2017) 247e259 [117] P. Ghasri, S. Gattu, N. Saedi, A.K. Ganesan, Chemical leukoderma after the application of a transdermal methylphenidate patch, J. Am. Acad. Dermatol. 66 (6) (2012) e237ee238. [118] D.J. Heal, S.C. Cheetham, S.L. Smith, The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety, Neuropharmacology 57 (7e8) (2009) 608e618.

259

[119] C.-U. Pae, H.-K. Lim, C. Han, A. Neena, C. Lee, A.A. Patkar, Selegiline transdermal system: current awareness and promise, Prog. Psychopharmacol. Biol. Psychiatry 31 (6) (2007) 1153e1163. [120] D.S. Robinson, J.D. Amsterdam, The selegiline transdermal system in major depressive disorder: a systematic review of safety and tolerability, J. Affect. Disord. 105 (1e3) (2008) 15e23.