Second Generation Antipsychotics

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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15020678

Orally administered antipsychotic drugs are the first-line treatment for psychotic disorders, such as schizophrenia and bipolar disorder. The most-used antipsychotic drugs include “atypical” or “second-generation” antipsychotics, such as quetiapine, risperidone, olanzapine, asenapine, lurasidone, zotepine, amisulpride or clozapine

antipsychotics bipolar disorder brain targeting nanosystems

1. Quetiapine Nanoemulsion

Boche et al. ^[1] evaluated the possibility of improving the brain delivery of quetiapine by developing a nanoemulsion for administration through the intranasal (IN) route. This biphasic dispersion was constituted of the following: an oil, Capmul^® MCM (medium-chain mono- and diglycerides); a non-ionic surfactant, Tween^® 80, with non-irritant properties for the nasal tissue; a cosurfactant/cosolvent, Transcutol^® P, which has the capacity to stabilize the nanoemulsion and increase the solubility of the active ingredient, and in combination with Tween^® 80, forms a less viscous nasal preparation; and also a second cosolvent, propylene glycol. The nanoemulsion was characterized for droplet size (144 nm), polydispersity index (PDI) (0.193), zeta potential (ZP) (−8.131 mV) and encapsulation efficiency (EE) (91%) and exhibited a small and homogeneous droplet size, neutral charge and high drug content, showing adequacy for increased system stability and intranasal administration. They also performed an in vivo pharmacokinetic study in rats, with both intravenous (IV) and IN administration of the developed nanoemulsion and a drug solution. It was observed that the brain concentration of quetiapine after the IN administration of the nanoemulsion was superior to that of the IN solution, resulting in a higher brain bioavailability. Furthermore, the time that it took to reach maximum drug concentration (T_max) in the brain was shorter for the IN nanoemulsion than for the IV administration, indicating a faster brain transport of quetiapine. Additionally, the plasma area under the curve (AUC) and maximum drug concentration (C_max) values following IN nanoemulsion administration were smaller and hence advantageous, as they indicate that there was a reduced systemic drug distribution and, consequently, a diminished likelihood of systemic adverse effects. Furthermore, it was determined that the drug reached the brain more effectively and directly with the IN nanoemulsion since the drug targeting efficiency (DTE%) (268%) and the direct transport percentage (DTP%) (64%) values were higher than those of the IN solution (141% and 29%, respectively), confirming the advantage of the IN administration of the developed quetiapine nanoemulsion, allowing an efficient brain targeting of the drug.

2. Risperidone Spanlastics, Nanoemulsions and Solid Lipid Nanoparticles

Abdelrahman et al. ^[2] conducted a study to investigate whether a spanlastics nanovesicle was suitable for risperidone brain targeting via intranasal delivery. The nanovesicular structure was made of a non-ionic surfactant (Span^® 60), a cosolvent (ethanol) and an edge activator (PVA). The use of PVA was beneficial for reducing the particle size and imparting elasticity to the nanovesicle. Characterization of the prepared nanovesicular system was undertaken, and it showed a mean particle size of 103.4 nm, a PDI of 0.341 and a ZP of −45.92 mV, all indicative of physical stability and the minimal possibility of aggregation of the prepared spanlastics. The reported EE was 64%, and it showed a relatively high viscosity of 70 cPs due to the presence of two viscous surfactants, with no need for the addition of gelling agents. An in vivo pharmacokinetic study was performed on rats, and the risperidone concentration in both brain and plasma was determined after the IN administration of the developed spanlastics and then compared to an IN solution of the drug. The spanlastics system exhibited both higher brain C_max and T_max values than the drug solution, indicating that a greater brain concentration was achieved, but it took longer to reach the brain. In addition, the DTE% (469%) and DTP% (79%) were higher for the IN spanlastics than for the drug solution (217% and 55%, respectively), further indicating the superiority of the developed nanosystem and the high partitioning of the drug to the brain via both the olfactory route and through the blood–brain barrier (BBB) (after systemic absorption). Additionally, the developed formulation proved to be safe for intranasal administration, showing high biocompatibility in a histopathological study (sheep nasal mucosa).

Furthermore, Đorđević et al. ^[3] designed two risperidone nanoemulsions for parenteral administration. The biphasic dispersions consisted of medium-chain triglycerides and purified soybean oil (oils), soy lecithin and sodium oleate (emulsifiers), benzyl alcohol (cosolvent), butylhydroxytoluene (antioxidant), glycerol (isotonic agent) and distilled water. Additionally, one of the nanoemulsions also contained polysorbate 80 (hydrophilic surfactant) in its composition. The characterization of the nanoemulsions revealed that both formulations had a favorable droplet size (around 184 nm), uniform size distribution (PDI of approximately 0.11) and high surface charge (ZP around −56 mV), suggestive of nanoemulsion stability with low viscosity (approximately 5 cP), which is especially desirable for IV administration. The results of the pharmacokinetic studies performed on rats after the intraperitoneal administration of either one of the developed nanoemulsions or a drug solution showed that both the brain and plasma AUC values were higher after the administration of the nanoemulsions in comparison to the drug solution. The differences in performance between the two nanoemulsions were not significant, and thus there was no influence due to the incorporation of polysorbate 80 into the composition of the formulation.

On the other hand, Qureshi et al. ^[4] formulated and optimized chitosan SLN for IN administration. The developed SNL consisted of oleic and stearic acids, distilled water, Tween^® 80 (surfactant) and a chitosan solution for coating. A small particle size (132.7 nm), high drug content (8%) and high in vitro drug release (81%) were obtained. In the in vivo pharmacokinetic study in rats, either the developed SLN or a risperidone suspension was administered through the IN or IV routes. The results showed that the SLN produced higher brain C_max and AUC values when compared to the IN and IV drug suspensions despite having a higher T_max (due to the controlled drug release of the drug from the SLN).

3. Olanzapine Solid Lipid Nanoparticles, Polymeric Nanoparticles, Nanostructured Lipid Carriers and Niosomes

Joseph et al. ^[5] conducted a study in which they developed solid lipid nanoparticles (SLNs) for the treatment of acute episodes of schizophrenia. Two different types of SLN were formulated, one consisting of glyceryl monostearate (solid lipid with surfactant capability), water and poloxamer 188 (hydrophilic surfactant), and another having the same composition but with an additional coating of Tween^® 80, with the intention that this additional coating would provide the SLNs with an increased brain targeting capability, crossing the BBB by means of endocytosis. The characterization of the nanosystems indicated that the presence of Tween^® 80 slightly reduced the values of both particle size (from 157.42 to 151.29 nm) and PDI (from 0.411 to 0.346). There was also a decrease in the ZP absolute value with the addition of the Tween^® 80 coating (from −37.25 to −33.67) owing to the adsorption of the non-ionic surfactant to the SLN surface. Moreover, the high ZP absolute values indicate the potentially good stability of these formulations. The developed nanosystems also had a high EE (73% and 75%) and drug content (around 4%) (without and with Tween^® 80, respectively). Given the similarities between the two SLNs, their in vitro drug release profiles were also quite similar, almost overlapping, showing a sustained drug release over a time period of 50 h. The in vivo pharmacokinetic study performed on rats found an increase in efficacy with the IV administration of both SLNs when compared to a drug solution. In particular, the Tween^® 80-coated SLN displayed higher plasma bioavailability when compared to the non-coated SLN and the drug solution (higher AUC and C_max). In vivo pharmacodynamic studies were also performed on rats. In the apomorphine-induced sniffing and climbing behavior study, the antipsychotic effect of both developed SLNs (inhibition of “continuous sniffing” behavior) was sustained for 48 h, while the antipsychotic effect of the drug solution only lasted 8 h. Additionally, Tween^® 80-coated SLN administration showed a lower sniffing score at all time points when compared to the non-coated SLN, evidencing a higher degree of inhibition and, therefore, higher therapeutic efficacy. In the weight gain study, a formulation was administered to each group of animals daily for 28 days, and the body weight was measured every other day. Animals to whom SLNs were administered demonstrated less weight gain than animals to whom the drug solution was administered, with the Tween^® 80-coated SLNs inhibiting weight gain to a greater extent than the non-coated SLNs. Hence, these results indicated that the Tween^® 80-coated SLNs successfully delivered olanzapine to the brain, having increased efficacy and potentially enabling the treatment of schizophrenia with reduced drug doses.

Natarajan et al. ^[6] also developed olanzapine SLNs for IV administration for the purpose of increasing therapeutic efficacy and reducing systemic side effects, allowing for reduced necessary drug doses. These SLNs were composed of tripalmitin (solid lipid), stearyl amine (positive charge inducer), Tween^® 80 (surfactant) and water. The developed nanosystem presented with a small and homogeneous particle size (particle size of 110.5 nm, PDI of 0.340), potentially good stability (ZP of +35.29 mV) and high drug content (EE of 96%). The in vivo pharmacokinetic study was performed on rats to whom either the olanzapine SLN or a drug suspension was administered. Following the IV administration of the SLN, the olanzapine plasma concentration was higher than the achieved after the IV administration of the drug suspension. The plasma drug concentration also remained constant until 6 h after SLN administration, whereas with the drug suspension, it reached a minimum value after 3 h due to a prolonged drug release from the SNL. Similarly, the developed SLN led to a 23-fold higher brain bioavailability than the drug suspension after 24 h, and hence the administration of the SLN led to much slower clearance and prolonged drug levels.

On the other hand, Joseph et al. ^[7] encapsulated olanzapine in nanoparticles (NPs), mainly in order to minimize the extrapyramidal adverse effects associated with its administration. Two different NPs were prepared, one with and one without a Tween^® 80 coating. The NPs were also made of polycaprolactone and poloxamer 188. The results of the characterization studies demonstrated that both NPs presented with particle sizes of less than 100 nm, thereby allowing a potentially better brain targeting of the nanosystem (73.28 and 81.41 nm, for the non-coated and coated NPs, respectively). The formulations also exhibited a relatively uniform size distribution, with a PDI of 0.231 and 0.312, a high EE of 79 and 77%, and a potentially high physical stability, with a ZP of −32.46 and −27.81 mV (non-coated and coated NP, respectively). The in vivo pharmacokinetic studies involving the IV administration of an olanzapine solution or the developed NPs to rats showed that the NPs led to higher brain and plasma C_max and AUC values than the drug solution. Furthermore, the Cmax obtained with the coated NPs was higher than with the uncoated counterpart. Thus, it was concluded that the developed NPs enhanced drug permeation across the BBB and that the coated NPs did so more significantly. The catalepsy pharmacodynamic study was also conducted on rats, with the animals to which the NPs were administered demonstrating a more significant inhibition of catalepsy than the drug solution group and with the coated NPs having a more significant effect.

In turn, Gadhave et al. ^[8] incorporated olanzapine into NLC for use in intranasal administration. The nanostructured lipid carriers (NLCs) were made of Labrafil^® M 1944 CS (liquid lipid), Compritol^® 888 ATO and Gelucire^® 44/14 (solid lipids) and Tween^® 80 (surfactant). Gelucire^® 44/14 was chosen since it has been shown to be able to inhibit efflux transporters, such as P-glycoprotein, thus potentially increasing brain drug bioavailability. Based on this core composition, they prepared a second formulation by adding two polymers in order to potentially extend the residence time of the preparation in the nasal cavity: hydroxypropyl methylcellulose K4M (HPMC, viscosifying and mucoadhesive agent) and poloxamer 407 (in situ gelling agent), hence making an NLC nanogel. The NLCs had a particle size of 88.95 nm, a PDI of 0.31, a EE of 89%, a drug loading of 6% and a ZP of −22.62 mV, thus having the required characteristics in terms of size, homogeneity, stability and drug content. In the in vivo pharmacokinetic study, the results showed that the IN administration of the NLC nanogel significantly increased the brain concentration of olanzapine when compared with the IV administration of the NLCs. Moreover, IV NLC administration revealed a greater accumulation of the drug at the administration site and in the systemic circulation, thus leading to a higher risk of hematological adverse effects. Therefore, the IN delivery of the NLC nanogel showed a capacity for olanzapine brain targeting. An in vivo safety study was undertaken wherein rats were given low (1 mg/kg), medium (2 mg/kg) and high (4 mg/kg) doses of the IN NLC nanogel over 28 days. The study revealed that all of the hematological parameters were within the normal physiological range, and hence the IN NLC nanogel did not provoke agranulocytosis or leukopenia in the animals, being potentially safe. This could be explained by the fact that the NLC nanogel contains a mucoadhesive polymer in its composition (HPMC) that helps retain the drug in the nasal cavity for a more prolonged time period, reducing the amount of drug that will be absorbed into the bloodstream and reducing the risk of adverse hematological effects. Additionally, a histopathological study of the nasal mucosa conducted under the same circumstances further confirmed that chronic administration of the NLC nanogel is safe since the microscopic images did not reveal any physiological, structural changes compared to the control group. Therefore, the developed NLC nanogel was shown to be both potentially effective and safe.

Khallaf et al. ^[9] prepared a different type of nanosystem for olanzapine brain targeting: chitosan coated niosomes, to be administered through the IN route. These were composed of a non-ionic surfactant, Span^® 80, cholesterol, and a chitosan coating. Characterization of the nanovesicles revealed a particle size of 250.1 nm and an EE of 72%. Subsequently, this group determined, using rats, the olanzapine pharmacokinetic parameters after administration of an olanzapine solution by the IV or IN route, and of the niosomes by the IN route. At first, the IV drug solution exhibited higher brain drug concentrations and AUC values than the IN formulations, which may have been due to the high transport of olanzapine through the BBB, by passive diffusion, as a result of an initially high plasma drug concentration resulting from the IV administration. However, over time the brain drug concentration that resulted from IN noisome administration increased significantly, resulting in significantly higher brain C_max and AUC values, when comparing to the IN and IV drug solutions. These findings could be attributed to the controlled release of the drug from the developed nanosystems, which might have led to an increased residence time of the drug in the rat nasal cavity due to the chitosan’s mucoadhesive properties. Since non-ionic surfactants are the predominant components of niosomes, a histopathological study was also carried out to observe whether it caused toxic effects at the application site of the nanovesicles and the nasal mucosa. Nevertheless, there were no signs of irritation, edema, hemorrhage, or necrosis in the analyzed histological structure, and hence the nanosystem was considered safe for IN administration.

4. Asenapine Nanostructured Lipid Carriers and Nanoemulgel

Singh et al. ^[10] explored the IN route for brain targeting of asenapine formulated into glycol chitosan coated NLC. The developed nanocarrier was composed of a liquid lipid (oleic acid), a solid lipid (glyceryl monostearate), water, Tween^® 80, and glycol chitosan, a product of the conjugation of chitosan with ethylene glycol. This conjugate has the advantage of being soluble at physiological pH, while plain chitosan is only soluble at acidic pH values. The formulation was characterized regarding particle size (184.2 nm), ZP (+18.83 mV), and EE (84%). The in vitro drug release assay showed that the developed NLC had a controlled release profile, and cell viability studies revealed the biocompatible nature of both drug and excipients. Plasma and brain pharmacokinetic parameters, after administration of an asenapine solution, by IV or IN route, or the NLC, via IN route, were determined in rats. No significant differences were observed between the plasma C_max and T_max values after IN administration of the drug solution and the NLC. However, significant differences were observed concerning IV solution administration, with it leading to a higher plasma C_max value, which indicates that IN administration decreased systemic drug exposure. Moreover, it was observed that asenapine brain concentration was higher after NLC IN administration, when compared to the IV and IN solutions, at all time points, being measurable up to 24 h, which is related to a potentially prolonged drug retention at the site of action and, hence, therapeutic effect. The authors justified these results by hypothesizing that the hydrophilic glycol chitosan chain and the existence of a Tween^® 80 coating on the NLC surface protected the drug from both enzymatic degradation and uptake by macrophages. Additionally, since asenapine has been reported to have a teratogenic potential in early pregnancy, an embryological and fetal toxicology study was carried out in female rats. In the group exposed to the asenapine solution there was a substantial decrease in the total number of living fetuses, as well as their size, contrarily to the group exposed to the NLC, in which the percentage of fetal malformations was significantly lower. Overall, it was therefore concluded that the encapsulation of asenapine in the developed NLC reduced its teratogenic potential, hence making it a safer option in terms of embryological toxic effects.

On the other hand, Kumbhar et al. ^[11] performed a study in order to optimize an asenapine mucoadhesive nanoemulsion, to promote its adhesion to the nasal mucosa and improve brain drug targeting. Thus, they developed a nanoemulgel constituted of an oil (Capmul^® PG-8), a surfactant (Kolliphor^® RH40), a cosurfactant (Transcutol^® HP), water and a gelling agent (Carbopol^® 971). The nanoformulation exhibited a droplet size of 21.2 nm and a PDI value of 0.355. Although a longer retention time of the formulation in the nasal cavity was intended, the developed nanoemulgel should not affect the normal functioning of the nasal cilia, especially for chronic therapeutic regimen purposes. Hence, the nasal ciliary toxicity of the developed nanoemulgel, as well as its nanoemulsion counterpart (same formulation but without the gelling agent, used for comparison purposes), were evaluated in the nasal mucosa of sheep. Since no morphological changes were observed for either formulation, the authors inferred that the drug and all used excipients were harmless to the nasal mucosa, and hence the developed formulations were safe for IN administration. Next, an in vivo pharmacokinetic study was performed on rats with the IN administration of either the nanoemulgel or the nanoemulsion or the IV administration of a drug solution. The results showed that brain C_max was reached faster with IN administration (1 h) when compared to the IV route (3 h). In addition, the IN nanoemulgel showed higher brain C_max and AUC values when compared to the IN nanoemulsion and IV solution. The high viscosity and mucoadhesion of the nanoemugel resulted in a prolonged residence time in the nasal cavity and, consequently, in reduced mucociliary clearance, which was reflected in the resulting higher brain drug levels. For the same reason, the IN nanoemulgel evidenced the highest pharmacokinetic ratios values when compared to the IN nanoemulsion, both in what concerns DTP% (80% and 73%, respectively) and DTE% (689% and 517%, respectively). Finally, three pharmacodynamic studies were performed, as follows: the catalepsy test, the induced locomotor activity test, and the paw test. The rats to which the nanoemulgel or the nanoemulsion were administered by the IN route showed a very similar cataleptic response, exhibiting no signs of catalepsy 6 h after drug administration. Locomotor count values were also similar for both formulations, leading to a significant reduction in locomotor activity due to the dopaminergic antagonist effect of asenapine. Particularly, in the paw test, there was no significant alteration in the forelimb retraction time (FRT) of the treated animals, indicating the absence of extrapyramidal adverse effects. Moreover, the prolongation of the hindlimb retraction time (HRT) was also representative of the potential antipsychotic effect of the developed asenapine IN formulations.

5. Lurasidone Nanostructured Lipid Carriers and Mixed Polymeric Micelles

Jazuli et al. ^[12] prepared NLCs for IN administration to improve the brain targeting of lurasidone. This developed lipid carrier was composed of a liquid lipid (Capryol^® 90, propylene glycol monocaprylate), a solid lipid (Gelot^TM 64, a mixture of glycerol monostearate and PEG-75 stearate), a surfactant (Tween^® 80) and a cosurfactant (Transcutol^® P), all of which were selected based on drug solubility capability and resulting nanosystem stability. The NLCs were characterized according to their particle size (207.4 nm), PDI (0.392) and encapsulation efficiency (EE) (92%). An in vivo pharmacokinetic study was conducted using rats to determine lurasidone brain distribution after IN NLC administration or after the administration of either an IN drug solution or an oral drug suspension. The developed IN NLCs were found to be more effective in increasing lurasidone brain bioavailability, leading to a higher brain C_max and AUC, a lower elimination rate constant and a longer half-life time than the other administered formulations. Moreover, IN administration led to a lower plasma drug concentration, minimizing extravascular drug distribution and, consequently, potential systemic side effects, making it a safer option than other routes of administration.

Pokharkar et al. ^[13] also developed a lurasidone IN nanosystem, in this case, mixed polymeric micelles (MPMs). The amphiphilic copolymers of Pluronic^® F127 and Gelucire^® 44/14 were employed to formulate the MPMs. The developed MPMs exhibited a particle size of 175 nm and an EE of 98%. In the in vivo pharmacokinetic study, either a drug solution or the developed MPMs were administered to rats by both IV and IN routes. The IN administration of the MPMs resulted in high lurasidone brain bioavailability, leading to a higher brain C_max and AUC than those obtained with all other formulations and administration routes, thereby indicating the effectiveness of the developed nanosystem in brain drug targeting through the IN route. Moreover, high DTE% (394%) and DTP% (74%) values proved that the IN administration of the developed MPMs allowed lurasidone brain targeting by direct transport through the olfactory and trigeminal nerve pathways.

6. Zotepine Nanosuspension

Pailla et al. ^[14] developed a zotepine nanosuspension intending to increase its brain targeting, thereby reducing the needed drug doses and, hence, decreasing dose-dependent side effects. The developed colloidal dispersion consisted of solid drug particles suspended in a solution containing surfactants, namely soy lecithin and Pluronic^® F-127, intended to increase drug permeability and decrease particle size and mucus viscosity, and a polymeric and mucoadhesive stabilizer, HPMC E15, with the capacity of increasing formulation stability (suspender function) and increasing the nanosuspension’s residence time in the nasal mucosa. The developed formulation revealed a particle size of 330 nm, a PDI of 0.208 and a ZP of 18.26 mV. The drug concentrations in the rat plasma and brain tissue samples were determined after the administration of either a zotepine solution, IV or IN, or the developed nanosuspension through the IN route. The results showed that the zotepine plasma concentration was highest after IV solution administration, then after IN solution administration, and significantly lower in the case of the IN nanosuspension, proving the IN route to be a potentially safer route with better brain drug targeting. This was confirmed by the brain drug levels since the developed IN nanosuspension displayed higher brain C_max and AUC values than the other formulations. Moreover, the IN nanosuspension exhibited the highest DTE% (33,712%) and DTP% (97%) values when compared to the IN solution, which further verified the promising potential of the developed formulation for brain drug targeting when administered through the IN route.

7. Amisulpride Nanoemulsion and Nanoemulgel

Gadhave et al. ^[15] produced, optimized, and investigated the therapeutic efficacy of a nanoemulsion and a nanoemulgel for the treatment of schizophrenia. The developed nanoemulsion was composed of an oil (Maisine^® CC, glyceryl monolinoleate), a surfactant (Labrasol^®), a cosurfactant (Transcutol^® HP) and water. The nanoemulgel had that same composition except for the addition of the in situ gelling agents of xanthan gum and poloxamer 407, which were added in order to increase the formulation’s retention at the administration site, minimizing the drug loss caused by mucociliary clearance and consequently increasing amisulpride absorption and brain delivery. Both the nanoemulsion and the nanoemulgel were subjected to droplet size (92.15 and 106.11 nm, respectively), PDI (0.46 and 0.51, respectively), ZP (−18.22 and −16.01 mV, respectively) and EE (99%) characterization. To determine the formulations’ pharmacokinetic profile, the nanoemulgel was administered via IN and the nanoemulsion was administered either via IN or IV to the rats. It was observed that the IN administration of both the nanoemulgel and the nanoemulsion led to higher brain drug concentrations than the IV route. Furthermore, the IN nanoemulgel led to the highest brain and lowest plasma C_max and AUC values. Thus, the pharmacokinetic data demonstrated that the IN administration of the developed nanoemulgel and nanoemulsion led to direct drug transport to the brain, with the nanoemulgel being the most effective. Additionally, the therapeutic efficacy of the developed amisulpride nanoformulations was also determined by the catalepsy test, the induced locomotor activity test and paw test studies. It was found that the rats treated with either the nanoemulgel or the nanoemulsion for 28 days did not demonstrate symptoms of catalepsy (compared to the control group). However, the nanoemulgel led to a lower catalepsy response than the nanoemulsion. This result could be justified by the rapid permeation and drug-modified release from the developed formulation. Furthermore, both formulations led to a significant reduction in locomotor activity, proving that the drug did, in fact, reach the intended therapeutic target, having antagonistic action on the brain’s dopamine D2 receptors. Additionally, the nanoemulgel showed a greater reduction in locomotor activity, therefore exhibiting greater therapeutic efficacy. Furthermore, the paw test revealed no major changes in the FRT; however, there was an extensive reduction in HRT in the animals to which the IN nanoemulgel or the IN nanoemulsion were administered, which reinforces the absence of extrapyramidal effects and the existence of therapeutic efficacy. Finally, the occurrence of toxicological symptoms and signs was evaluated through hematological and pathology analyses. In these studies, the authors concluded that the IN nanoemulgel did not cause any hematological toxicity, whereas the IV nanoemulsion led to dose-dependent toxic effects, leading to the deaths of those animals in which doses of 5 mg/kg were administered, which was further proof of the higher safety of the IN route as well as the superiority of the developed amisulpride nanoemulgel.

8. Clozapine Nanosuspension

In light of all the problems associated with clozapine oral administration, such as low solubility and low dissolution rates, high gastrointestinal and hepatic metabolism and consequent low cerebral bioavailability, Patel et al. ^[16] developed a clozapine nanosuspension for IN administration. The nanosuspension was prepared by dispersing solid powder particles of the drug in deionized water containing D-α-tocopheryl polyethylene glycol succinate 1000 (TPGS) and polyvinylpyrrolidone K30 as surfactants and formulation stabilizers. TPGS also has the reported ability to inhibit efflux transporters, such as P-glycoprotein, thus increasing drug bioavailability. The nanosuspension exhibited a small particle size (281 nm), thus leading to a high dissolution rate and surface area for permeation, and a ZP of −0.83 mV, due to the non-ionic nature of TPGS, adsorbed to the surface of the particles. The in vitro drug release assay showed that the nanosuspension had a faster and overall higher drug release than that of a conventional drug suspension. The in vivo pharmacokinetic study using rats demonstrated that the IN nanosuspension substantially increased clozapine brain concentration when compared to the conventional oral suspension, displaying significantly higher C_max and AUC values. Additionally, a nasal ciliary toxicity study proved the suitability of the nanosystem for IN administration.

References

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Subjects: Nanoscience & Nanotechnology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Maria Daniela Ferreira

Joana Duarte

Francisco Veiga

Ana Cláudia Paiva-Santos

Patrícia C. Pires

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