Aripiprazole (ARZ) is an atypical antipsychotic drug used to treat a variety of mood and psychotic disorders, such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Although ARZ offers significant therapeutic benefits, its poor solubility in water requires the development of delivery systems aimed at improving the solubility and bioavailability of the drug. In this work, cryogels based on two natural products-agar and β-cyclodextrin (CD)-were developed and evaluated as a drug delivery system for ARZ. The cryogels were prepared by cryogenic treatment of aqueous solutions of agar and the β-CD/ARZ complex, followed by thawing. The main characteristics of the material, including gel fraction yield, swelling degree, pore volume, elastic properties, and morphology were studied in detail. The release of ARZ from composite cryogels was assessed in two media resembling the pH in stomach and intestine. The system exhibited a pH-dependent release of ARZ, with a slower rate in acidic media (pH 1.2) than in the neutral phosphate buffer (pH 6.8). Under in vitro conditions, the amount of released ARZ over 48 h reached 33%.

Drug repurposing provides a cost-effective and time-saving approach to cancer therapy. Aripiprazole (ARI), a third-generation antipsychotic, has shown potential anticancer properties by modulating pathways central to tumor progression and resistance. This scoping review systematically examines evidence on ARI's anticancer effects, mechanisms of action, and translational potential. A systematic search of PubMed, EMBASE, SCOPUS, and Web of Science was conducted following PRISMA-ScR guidelines. Eligible studies included invitro, invivo, and clinical investigations. Data on cancer types, pathways, assays, and outcomes were extracted and synthesized to identify trends and gaps. Of 588 screened studies, 23 met inclusion criteria, spanning cancer types such as breast, colorectal, lung, and brain cancers. ARI modulates key pathways like PI3K/AKT/mTOR and Wnt/β-catenin, induces apoptosis through mitochondrial dysfunction and ER stress, and overcomes drug resistance by inhibiting P-glycoprotein activity and expression. It exhibits tumor-suppressive effects invivo and synergizes with chemotherapy and radiotherapy. Retrospective population studies suggest ARI's prolactin-sparing properties may reduce the risk of hormone-sensitive cancers such as breast and endometrial cancer compared to antipsychotics with stronger dopamine receptor blockade. Additionally, ARI's ability to target multiple Hallmarks of Cancer highlights its promise as a repurposed anticancer agent. However, current evidence is primarily preclinical and observational, with limited clinical validation. Large-scale cohort studies and prospective trials are essential to confirm its efficacy and address translational challenges. By bridging these gaps, ARI could emerge as a valuable adjunctive therapy in oncology, leveraging its safety profile and versatility to address unmet needs in cancer treatment.

Natural polymers have emerged as versatile and sustainable alternatives to synthetic polymers in pharmaceutical and biomedical applications. This study focuses on the extraction of arabinoxylan (AX) from maize husk and its potential as a promising excipient to enhance the solubility and oral bioavailability of Aripiprazole (APZ), a poorly water-soluble antipsychotic drug, offering a robust strategy for overcoming challenges associated with hydrophobic drugs. APZ-loaded AX nanoparticles were synthesized using the ionotropic gelation technique. The formulation with the highest encapsulation efficiency designated as FN4 was selected for detailed characterization. Various analytical techniques, including Scanning Electron Microscopy (SEM), X-ray Diffraction (XRD), and Differential Scanning Calorimetry (DSC), were employed to assess the morphological, crystalline, and thermal properties of the nanoparticles. In vitro release studies were conducted on both simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) to evaluate drug dissolution behaviour. The everted sac method was utilized to assess the permeation and transport of APZ from the AX-based nanoparticles. The FN4 formulation exhibited an encapsulation efficiency of 88.9% ± 1.77%, with a particle size of 284.4 nm, a polydispersity index (PDI) of 0.346, and a zeta potential of 20.7 mV. SEM analysis revealed a uniform distribution of polyhedral-shaped nanoparticles. XRD and DSC analyses indicated that APZ was in an amorphous state within the nanoparticles. Drug release was more pronounced at pH 6.8, with the AX nanoparticles showing sustained release. The everted sac method demonstrated enhanced permeation of APZ across intestinal membranes, supporting the potential of AX nanoparticles in improving drug absorption. The AX-based nanoparticle formulation significantly improved the solubility, pH-dependent release profile, and sustained release of APZ, offering a promising strategy to enhance the oral bioavailability of poorly soluble drugs. These findings suggest that AX nanoparticles could serve as an effective delivery system for enhancing the therapeutic potential of hydrophobic drugs like APZ.

Aripiprazole (ARI) is an atypical antipsychotic which is a substrate of P-glycoprotein (P-gp), a transmembrane glycoprotein that plays a crucial role in eliminating potentially harmful compounds from the organism. ARI once-monthly (AOM) is a long-acting injectable form which improves treatment compliance. Genetic polymorphisms in ABCB1 may lead to changes in P-gp function, leading to individual differences in drug disposition. The present study aims to determine how the different variants of the three most prevalent SNPs of the ABCB1 gene affect plasma concentrations of ARI, of its active metabolite dehydroaripiprazole (DHA) and ARI/DHA ratio in patients under AOM treatment. The metabolizing state of the two main aripiprazole metabolizing enzymes (CYP2D6 and CYP3A4) were considered to specifically study the effect of P-gp on plasma concentrations of the parent compound and its active metabolite. The study found a clear relationship between the genotypes found for the different ABCB1 SNPs and the ARI/DHA ratio. Specifically, patients with GG genotype in G2677T have almost twice the ratio compared to TT genotype. Similarly, this increase is also found in C3435T with 1.4-fold and in C1236T with 1.6-fold for the same genotypes. Regarding haplotypes, significant differences were obtained between CC-GG-CC and TT-TT-TT patients, with an 87.9% higher ratio in patients with the CC-GG-CC haplotype. There was a clear trend towards lower ARI concentrations and higher DHA concentrations when the presence of mutated T alleles increases. The ABCB1 gene could be a good partner along with CYP2D6 and CYP3A4 genotyping in conjunction with monitoring ARI plasma concentrations.

Neonatal growth and development are significantly influenced by maternal care and breastfeeding. Our previous research showed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in dams reduced prolactin (PRL) levels, nursing behavior, and milk production during lactation. Intracerebroventricular infusion of PRL in TCDD-exposed dams partially reversed these defects in mothers and offspring. However, the mechanism by which maternal TCCD exposure causes reduced PRL levels and multigenerational effects remains unclear. This study aimed to investigate the multigenerational effects of maternal TCDD exposure and sought solutions to the developmental issues arising from low PRL levels due to TCDD exposure during gestation. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 (F0 dams) led to decreased PRL concentrations in female offspring (F1/F2) and impaired maternal licking behavior when F1 females had given birth, resulting in adverse effects on body weight and short-term memory in F2/F3 offspring. Aripiprazole (ARI), a partial dopamine D2 receptor (D2R) agonist, increases PRL levels by inhibiting the effect of dopamine during PRL synthesis and secretion. Importantly, administration of ARI to F0 dams not only restored PRL levels, nursing behavior, and milk volume in the treated mothers but also mitigated the developmental deficits observed in F2/F3 offspring. These findings highlight the critical role of PRL in maternal care and offspring development and suggest that ARI could be a potential therapeutic intervention to mitigate the effects of TCDD-induced multi-generational developmental disruptions.

A graphene-based supramolecular gel was designed and prepared to control the crystallization process and polymorphism of pharmaceuticals. The gelators were modified at the end segments with pyrene moieties, which spontaneously interact with the graphene surface by aromatic stacking interaction resulting in a graphene-incorporated supramolecular gel linked by noncovalent interactions between urea groups. When graphene was included into the gel, the critical gel concentration and system rigidity changed significantly, fluorescence spectroscopy determined the close π-π stacking interaction between the gelator and graphene, and the material was confirmed as a true nanocomposite gel system by electron microscopy. Further the graphene was oxidatively modified to obtain hydroxylated graphene (Gr-OH), which was successfully incorporated into the gel system to serve as a medium for pharmaceutical crystallization. Glycine (GLY), caffeine (CAF) and aripiprazole (APZ) were selected as model drugs for gel surface crystallization and gel phase crystallization by Gr-OH hybrid gels. Incorporation of Gr-OH in the gel allowed close interaction by hydrogen bonding with drug molecules, resulting in different polymorphs of GLY, CAF and APZ compared to solution crystallization and shorter induction time of CAF compared to the native gel.

Aripiprazole (ARP) having lowest water solubility indicates class II drugs of BCS. These classes of drugs could potentially exhibit dissolution rate limited absorption. The objective of the present study is to improve the solubility and dissolution of Aripiprazole through solid dispersion (SD) technique. ARP-SDs were prepared by Kneading (KNE), Solvent evaporation (SE), Melt solvent (MS) and Microwave irradiation (MW) methods using PEG 4000, PEG 6000 at 1:1, 1:4 ratios. ARP-SDs were studied in solution state by solubility, in vitro dissolution rate and solid state by FTIR, XRD, and relative dissolution parameters through PCP Disso V3 software. The FTIR studies indicate no interaction in all the ARP-SDs, the powder XRD studies indicate lot of decrement in the principle peak heights of ARP in ARP-SDs suggest the transformation of crystalline ARP into nearer amorphous state predicting micronization mechanism. The solubility was improved linearly with increase in concentrations PEG 4000 and PEG 6000. The amount of ARP release from ARP-SDs prepared by KNE were found to be greater than other ARP-SDs and was in the order KNE>SE>MS >MW >PM>ARP. The dissolution of ARP-SDS, obeyed first order kinetics and model fitted with Hixon crowel. One-way ANOVA results suggest the DP60, and DE60 values were significantly higher (P<0.01) in ARP-SDS than pure drug. The result concludes that solid dispersion technique was can be used increase the solubility and dissolution of poorly soluble drug Aripiprazole.

ObjectiveSchizophrenia is a severe and chronic mental disorder that significantly impacts cognitive, social, and occupational functions, leading to substantial economic burdens. Long-acting injectable (LAI) antipsychotics have been introduced to improve treatment adherence and outcomes, yet their economic impact remains debated. We aim to analyze the impact of LAIs on the medical costs of Korean schizophrenia patients.MethodsA retrospective analysis of 164 schizophrenia patients treated with LAI antipsychotics, paliperidone palmitate, and aripiprazole monohydrate at Korea University Guro Hospital between January 2017 and July 2022 was performed. Comparisons of inpatient department (IPD) and outpatient department (OPD) healthcare expenditures one year before and after LAI initiation were conducted.ResultsLAIs led to an increase in annual OPD costs (1,437.44 ± 1,127.60 to 4,015.42 ± 1,204.59; units 1,000 KRW) but significantly reduced IPD admission associated costs (3,826.06 ± 5,500.63 to 698.06 ± 3,619.38; units 1,000 KRW). After LAI administration, there was an overall reduction in total annual healthcare costs (5,263.49 ± 5,333.11 to 4,713.48 ± 3,625.89; units 1,000 KRW), but it was not statistically significant.ConclusionAlthough the use of LAIs did not significantly lower the first-year medical costs of schizophrenia patients, they offer beneficial economic impacts over time by reducing hospitalization-associated costs. Future research should focus on long-term cost analyses and the impacts of newer LAI formulations.

The objective of this study was to investigate the physicochemical properties, drug release and in situ depot-forming behavior of alginate hydrogel containing poorly water-soluble aripiprazole (ARP) for achieving free-flowing injectability, clinically accessible gelation time and sustained drug release. The balanced ratio of pyridoxal phosphate (PLP) and glucono-delta-lactone (GDL) was crucial to modulate gelation time of the alginate solution in the presence of calcium carbonate. Our results demonstrated that the sol state alginate hydrogel before gelation was free-flowing, stable and readily injectable using a small 23 G needle. In addition, the ratio (w/w) of PLP and GDL altered the gelation time, which was longer as the PLP content increased but shorter as the GDL content increased. The alginate hydrogel with a ratio of PLP to GDL of 15:9 had the optimal physicochemical properties in terms of a clinically acceptable gelation time (9.1 min), in situ-depot formation with muscle-mimicking stiffness (3.55 kPa) and sustained release over a two-week period. The alginate hydrogel, which is tunable by varying the ratio of PLP and GDL, could provide a controllable pharmaceutical preparation to meet the need for long-acting performance of antipsychotic drugs like ARP.

Prolonged use of atypical antipsychotics (AAPs) is commonly associated with increased cardiovascular disease risk. While weight gain and related health issues are generally considered the primary contributors to this risk, direct interference with mitochondrial bioenergetics, particularly in the liver where these drugs are metabolized, is emerging as an additional contributing factor. Here, we compared the effects of two AAPs with disparate metabolic profiles on the response of Fao hepatoma cells to oxidative stress: olanzapine (OLA), which is obesogenic, and aripiprazole (ARI), which is not. Results showed that cells treated with ARI exhibited resistance to H2O2-induced oxidative stress, while OLA treatment had the opposite effect. Despite enhanced survival, ARI-treated cells exhibited higher apoptotic rates than OLA-treated cells when exposed to H2O2. Gene expression analysis of pro- and anti-apoptotic factors revealed that ARI-treated cells had a generally blunted response to H2O2, contrasting with a heightened response in OLA-treated cells. This was further supported by the reduced activation of MAPKs and STAT3 in ARI-treated cells in response to H2O2, whereas OLA pre-treatment enhanced their activation. The loss of stress response in ARI-treated cells was consistent with the observed increase in the mitochondrial production of O2•-, a known desensitizing factor. The physiological relevance of O2•- in ARI-treated cells was demonstrated by the increase in mitophagy flux, likely related to mitochondrial damage. Notably, OLA treatment protected proteasome activity in Fao cells exposed to H2O2, possibly due to the better preservation of stress signaling and mitochondrial function. In conclusion, this study highlights the underlying changes in cell physiology and mitochondrial function by AAPs. ARI de-sensitizes Fao cells to stress signaling, while OLA has the opposite effect. These findings contribute to our understanding of the metabolic risks associated with prolonged AAP use and may inform future therapeutic strategies.

Aripiprazole once-monthly (AOM) exhibits an important interindividual pharmacokinetic variability with significant implications for its clinical use. CYP2D6 and CYP3A4 highly contributes to this variability, as they metabolize aripiprazole (ARI) into its active metabolite, dehydroaripiprazole (DHA) and the latter into inactive metabolites.This study aims to evaluate the effect of CYP2D6 and CYP3A4 polymorphisms in combination and the presence of concomitant inducers and inhibitors of this cytochromes on ARI and DHA plasma concentrations in a real clinical setting.An observational study of a cohort of 74 Caucasian patients under AOM treatment was conducted. Regarding CYP2D6, higher concentrations were found for active moiety (ARI plus DHA) (AM) (67 %), ARI (67 %) and ARI/DHA ratio (77 %) for poor metabolizers (PMs) compared to normal metabolizers (NMs). No differences were found for DHA.PMs for both CYP2D6 and CYP3A4 showed a 58 % higher AM and 66 % higher plasma concentration for ARI compared with PMs for CYP2D6 and NMs for CYP3A4. In addition, PMs for both CYP2D6 and CYP3A4 have 45 % higher DHA concentrations than NMs for both cytochromes and 41 % more DHA than PMs for CYP2D6 and NMs for CYP3A4, suggesting a significant role of CYP3A4 in the elimination of DHA.Evaluating the effect of CYPD26 and CYP3A4 metabolizing state in combination on plasma concentrations of ARI, DHA and parent-to-metabolite ratio, considering concomitant treatments with inducers and inhibitor, could optimize therapy for patients under AOM treatment.

BackgroundReducing falls and fractures remains an important clinical goal in managing older residents with Parkinson’s disease psychosis (PDP) in long-term care/nursing home (LTC/NH) settings.ObjectivesThis analysis examined risk of all-cause falls or fractures among PDP residents on continuous monotherapy with pimavanserin (PIM) versus (i) other atypical antipsychotics (AAPs) [quetiapine (QUE), risperidone (RIS), olanzapine (OLA), aripiprazole (ARI)] and (ii) QUE.MethodsA retrospective analysis of parts A, B, and D claims from a 100% Medicare sample (2013–2019) in LTC/NH settings was conducted. LTC/NH residents in the USA initiating continuous monotherapy (PIM versus other AAPs; PIM versus QUE) for ≥ 6 months between 01 January 2014 and 31 December 2018 were 1:1 propensity score matched (PSM) on 31 variables (age, sex, race, region, and 27 Elixhauser comorbidities). Outcomes included three measures: risks of falls only, fractures only, and falls/fractures during 6-months follow-up. Demographic characteristics were described using chi-square and t-tests. Generalized linear models were used to assess difference in risks of falls/fractures.ResultsOf 7187 residents, 47.59% (n = 3420) were female and mean age was 78.8 (± 7.75) years. In total, 14% (n = 1005) were on PIM and 86% (n = 6182) were on other AAPs. After PSM, falls only among PIM residents (n = 1005) was 4.58% (n = 46) versus 7.66% (n = 77) for other AAPs (n = 1005) [relative risk (RR) = 0.60 (0.42, 0.85), p < 0.05] and 8.26% (n = 83) for QUE (n = 1005) residents (p < 0.05). Fractures only among PIM residents was 1.39% (n = 14) compared with 2.09% (n = 21) for other AAPs (p = 0.31) and 1.89% (n = 19) for QUE (p = 0.49), respectively. Taken together, falls/fractures among PIM residents were 5.67% (n = 57) versus 9.05% (n = 91) for other AAPs [RR = 0.63 (0.46, 0.86), p < 0.05] and 9.55% (n = 96) for QUE (p < 0.05), respectively.ConclusionsIn this analysis of LTC/NH residents with PDP, PIM had a 37% and 41% lower risk of all-cause falls/fractures versus other AAPs and versus QUE, respectively.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-024-00433-2.

Background:This study’s objective was to investigate the adverse effects of atypical antipsychotics (AAPs) on the metabolic, hematological, and endocrinological systems in the inpatient environment for children and adolescents with diverse psychiatric disorders.Methods:A retrospective assessment of 208 children’s and adolescents’ medical records was conducted. All patients were on AAP monotherapy. At baseline and after treatment, measurements of body weight, height, body mass index (BMI), BMI z-score, fasting blood glucose (FBG), total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, complete blood count, liver functions, thyroid functions, and prolactin levels were made. Scores from the Children’s Global Assessment Scale (CGAS) and the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) were preserved.Results:The overall patient population had a mean age of 14.50 ± 2.32 years, 139 girls, and 69 boys. Of the patients, 63 (30.29%) were on risperidone (RIS), 69(33.17%) were on aripiprazole (ARI), 32 (15.39%) were on quetiapine (QUE), 42 (20.19%) were on olanzapine (OLA), and 2 (0.96%) were on clozapine (CLO). In the OLA group, the BMI and BMI z-score increased more than in the RIS, QUE, and ARI groups (P = .030, P = .014, and P = .001, respectively) (P = .001). The mean difference in CGAS and HoNOSCA between the start of antipsychotic medication and hospital discharge was statistically different for all four groups (P = .001 for all). The mean FBG levels in the OLA group increased statistically significantly (P = .013, P = .021) in contrast to the RIS group. In addition, a statistically significant difference in triglycerides across the groups was found (P = .003).Conclusion:According to the findings of our study, children and adolescents appear to be at a significant risk for psychotropic-induced PRL increase, weight gain, metabolic, and hematological consequences. To prevent serious health problems, a meticulous risk–benefit assessment for AAPs treatment should be done between clinicians and patients and their families.

Antipsychotic drugs (APDs) are used to treat many psychiatric illnesses as schizophrenia. Typical antipsychotic drugs (TAPDs) are being used; however, they have many side effects. Atypical antipsychotic drugs (AAPDs) are newer medications with known fewer side effects. Aripiprazole (ARI) is an AAPD, recommended by healthcare providers, even during pregnancy. It can cross the placental barrier and enter fetal circulation, so it might be possible that ARI can adversely impair normal placental development and growth, if it is given prenatally. ARI was applied orally to pregnant female rats in two doses (3& 6mg/kg body weight). On gestation day 20, the mothers were sacrificed, and the placentas were removed and processed for general histological and electron microscopic evaluations. Immunohistochemistry was done using anti-PCNA (proliferating cell nuclear antigen), anti-Bax (for apoptosis) and anti-vascular endothelial growth factor alpha (VEGFA). Morphological evaluation revealed degenerative changes in the placenta as dark nuclei, vacuolization, and cyst formation. Ultra-structurally, there was degeneration of cellular components including organelles and nuclei. These changes were found in different cells of the basal and labyrinth zones and were dose dependent. Immunohistochemistry revealed upregulation of Bax and VEGFA and downregulation of PCNA. Prenatal administration of the AAPD, ARI to pregnant female rats resulted in histological changes in the placenta. Additionally, there was a decrease in cellular proliferation and increase in apoptosis, and vascular impairment. This indicates placental atrophy and dysgenesis and might suggest possible teratogenic effects to ARI, which needs further evaluation.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus—An aripiprazole case study

Anti-inflammatory and protective effects of Aripiprazole on TNBS-Induced colitis and associated depression in rats: Role of kynurenine pathway

Up to 34% of patients with schizophrenia are resistant to several treatment trials. Lack of continuous and adequate treatment is associated with relapse, rehospitalization, a lower effect of antipsychotic therapy, and higher risk of side effects. Long-acting injectables antipsychotics (LAI APs) enhance compliance and improve clinical outcomes and quality of life in patients with schizophrenia, and thus it may be advisable to administer two LAI APs at the same time in cases of treatment-resistant schizophrenia. The purpose of this review is to summarize the available literature regarding the combined use of two LAI APs in patients with schizophrenia or other psychotic spectrum disorders. An extensive literature search for relevant articles regarding any combination of two long-acting injectable antipsychotics has been performed from inception up to 9 February 2024, on PubMed, Scopus and APA PsycInfo, according to the PRISMA statement. Only studies reporting combination of two LAI APs and its clinical outcome in patients with schizophrenia and related disorders were selected. After the selection process, nine case reports, four case series and two observational retrospective studies were included in the final analysis. All patients treated with dual LAI APs reported a good response, and no new or unexpected adverse effects due to the combination of two LAIs were reported. Different drug combinations were used, and the most frequent association resulted in aripiprazole monohydrate + paliperidone palmitate once monthly (32 times). Our review highlights that the treatment regimen with two concurrent LAI APs is already widely used in clinical practice and is recognized as providing a promising, effective, and relatively safe therapeutic strategy for treating the schizophrenia spectrum disorders.

The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The investigations performed utilizing differential scanning calorimetry and broadband dielectric spectroscopy reveal that silica can play different roles depending on its concentration in the system with amorphous ARP. At low MS content, it activates recrystallization of the active pharmaceutical ingredient and supports forming the III polymorphic form of ARP. At intermediate MS content (between ca. 27 and 65 wt %), MS works as a recrystallization inhibitor of ARP. At these concentrations, the formation of III polymorphic form is no longer favorable; therefore, it is possible to use this additive to obtain ARP in either IV or X polymorphic form. At the same time, employing MS in concentrations >65 wt % amorphous form of ARP with high physical stability can be obtained. Finally, regardless of the polymorphic form it crystallizes into, each composite is characterized by the same temperature dependence of relaxation times in the supercooled and glassy states.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

Aripiprazole (ARZ) is a medication used for the treatment of various diseases such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Despite its therapeutic benefits, ARZ is characterized by a poor water solubility which provoked the development of various delivery systems in order to enhance its solubility. In the present work, a nanoscale drug delivery system based on N,N-dimethylacrylamide (DMAA) and β-cyclodextrin triacrylate (β-CD-Ac3) as potential aripiprazole delivery vehicles was developed. The nanogels were synthesized by free radical polymerization of DMAA in the presence of β-CD-Ac3 as a crosslinking agent and then loaded with ARZ via host-guest inclusion complexation. The blank- and drug-loaded nanogels were evaluated using different methods. Fourier transform infrared (FTIR) spectroscopy was employed to confirm the incorporation of β-CD moieties into the polymer network. Dynamic light scattering (DLS) was used to study the size of the developed systems. The samples exhibited a monomodal particle size distribution and a relatively narrow dispersity index. The hydrodynamic diameter (Dh) of the gels varied between 107 and 129 nm, with a tendency for slightly larger particles as the β-CD-Ac3 fraction increased. Loading the drug into the nanocarrier resulted in slightly larger particles than the blank gels, but their size was still in the nanoscopic range (166 to 169 nm). The release profiles in PBS were studied and a sustained release pattern with no significant burst effect was observed. A cytotoxicity assessment was also conducted to demonstrate the non-toxicity and biocompatibility of the studied polymers.