Boosting the In Vivo Transdermal Bioavailability of Asenapine Maleate Using Novel Lavender Oil-Based Lipid Nanocapsules for Management of Schizophrenia.

Lipid nanocapsules (LNCs) are promising for transdermal drug delivery due to their higher permeability-enhancing effects compared to polymeric nanoparticles. Lavender oil is an essential oil consisting of several terpenes (primarily linalool and linalyl acetate) known for their profound permeation-enhancing action. In the present work, we successfully encapsulated asenapine maleate (a second-generation antipsychotic that is highly metabolized by the liver, reducing its oral bioavailability) into biocompatible LNCs for transdermal application using a novel oily phase, i.e., lavender oil (LO-LNCs). A comparative study was conducted to determine the effects of different oily phases (i.e., Miglyol® 812, Labrafil® M1944CS, and Labrafac™ PG) on the LNCs. Surfactant types (Kolliphor® HS15, Kolliphor® EL and Tween80) and oil:surfactant ratios were studied. Blank and asenapine-loaded LNCs were optimized for particle size, polydispersity index, zeta potential, drug content and ex vivo skin permeation. Lavender oil and Labrafil® showed smaller vesicular sizes, while LO-LNCs increased the permeation of ASP across rat skin. In vivo pharmacokinetics revealed that LO-LNCs could increase the ASP Cmax via transdermal application by fourfold compared to oral suspension. They increased the bioavailability of ASP by up to 52% and provided sustained release for three days. The pharmacokinetic profile of the LO-LNCs was compared to ASP-loaded invasomes (discussed in a previous study) to emphasize LNCs' transdermal delivery behavior.

Determination of Asenapine Maleate in Pharmaceutical and Biological Matrices: A Critical Review of Analytical Techniques over the Past Decade.

Asenapine maleate is a second-generation atypical antipsychotic agent used in the treatment of schizophrenia, a neuropsychiatric disorder. It is available as a fast-dissolving sublingual tablet to avoid extensive first-pass metabolism with higher bioavailability as compared to oral formulations. Although, the established therapeutic solutions do not sufficiently satisfy the patient's safety and efficacy needs. Thus, the core research emphasis is to investigate strategies to produce novel formulations with enhanced safety and efficacy. This necessitates the development of robust, precise, and accurate methods for quantification of asenapine maleate in different sample matrices. Given the foregoing information, the current analysis concentrates on the different analytical techniques used to assess asenapine maleate in bulk, pharmaceutical formulations, and biological specimens. Reverse-phase HPLC coupled with UV detection is a majorly (nearly 50% of papers investigated) used technique for the estimation of asenapine maleate in formulations. On the other hand, for its quantification in the biological matrix, hyphenated techniques using mass spectrometry are widely used. This critical review reveals different analytical methodologies, including spectrophotometric, chromatographic, capillary electrophoresis techniques reported from 2011 to 2020, for the measurement of asenapine maleate in various sample matrices. The information presented in this review would be useful in future research for robust analytical method development for asenapine maleate utilizing a more scientific and risk-based approach. Also, it would aid to minimize analytical failure as well as method fine-tuning throughout the product life cycle. Further, this review may also direct scientists toward the development of methodologies for green research.

Enhancement of the Solubility of Asenapine Maleate Through the Preparation of Co-Crystals.

BACKGROUND: Asenapine maleate, an anti-schizophrenic drug, is a class II drug with low solubility and high permeability. This exerts a rate-limiting effect on drug bioavailability. OBJECTIVE: To improve the solubility/dissolution rate of asenapine maleate and hence the bioavailability using the co-crystal approach. METHODS: Co-crystals were prepared using the solvent evaporation method. Since the drug has Hbond acceptor count of 6, and H-bond donor count of 2, several co-formers (nicotinamide, urea, succinic, benzoic, and citric acid) were investigated in different ratios. The optimized co-crystals (drug-nicotinamide in a ratio of 1:3) were evaluated using PXRD, DSC, FTIR spectroscopy, and SEM. Additionally, in vitro dissolution and stability studies were conducted. RESULTS: Preparation of the co-crystals was successful except when citric and benzoic acids were used. PXRD patterns showed that the co-crystals were crystalline. FTIR spectroscopy confirmed the formation of H-bond between the drug and the co-former. DSC indicated a lower melting point than that of the components followed immediately by an exothermic peak, which confirmed the formation of co-crystals. SEM showed the formation of crystals with different size and habit. The dissolution of the drug from all the prepared co-crystals was almost similar and much enhanced compared to that of the unprocessed drug. The initial dissolution of the drug from the optimized batch was much faster than that from the other co-crystals and the physical mixture with the same ratio. The optimized batch exhibited long term stability. CONCLUSION: Co-crystals with improved solubility/dissolution rate of asenapine maleate were prepared successfully and were expected to enhance the bioavailability of the drug.

Design of long acting invasomal nanovesicles for improved transdermal permeation and bioavailability of asenapine maleate for the chronic treatment of schizophrenia.

Asenapine Maleate (ASPM) is a second generation antipsychotic used for the management of schizophrenia but with very limited oral bioavailability due to its extensive first pass metabolism. Transdermal administration of ASPM using nanocarriers like invasomes might offer an excellent alternative to its oral administration with enhanced bioavailability and a sustained action. ASPM-loaded invasomes were successfully prepared by thin film hydration technique; meanwhile the penetration enhancing effect of terpenes (cineole and limonene) was compared to hydromiscible cosolvent (Transcutol®). Soft nanovesicles containing Transcutol® displayed smaller particle sizes than invasomes containing limonene and cineole while invasomes showed higher efficiency to encapsulate asenapine. Ex- vivo skin permeation revealed that invasomes with limonene are more efficient than those with cineole for the transdermal delivery of asenapine. The optimum nano-invasomes formulation contained 1% Limonene and showed particle size of 82 ± 0.6 nm, entrapment efficiency of 56.6 ± 1.5 % and transdermal flux of 3401.6 ± 604.2 (µg/h.cm2). Transmission electron microscopy of the selected formulation showed uniform spherical vesicles with intense outline and lighter core and FTIR study emphasized that ASPM was completely incorporated within the vesicles. The in- vivo pharmacokinetic study revealed that transdermal invasomes achieved 2 folds higher Cmax compared to oral suspension and delayed the Tmax from 1.5 h to around 4 h. The bioavailability of asenapine loaded invasomes after transdermal application was significantly improved to 54.5% compared to the 3.6 % achieved with the oral administration and exceeding the bioavailability of sublingual tablets currently available in the market and exhibited sustained release kinetics over 72 h which permits reduction of dosing frequency to increase patient adherence to medication.

Asenapine maleate inhibits angiotensin II-induced proliferation and activation of cardiac fibroblasts via the ROS/TGFß1/MAPK signaling pathway.

BACKGROUND: Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis. METHODS: Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFß1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected. RESULTS: After Ang II stimulation, TGFß1, TGFß1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFß1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFß1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFß1/MAPK signaling pathway. CONCLUSIONS: This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFß1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis.

Surface-engineered nanoliposomes with lipidated and non-lipidated peptide-dendrimeric scaffold for efficient transdermal delivery of a therapeutic agent: Development, characterization, toxicological and preclinical performance analyses.

The current study aimed to develop novel peptide dendrimer (PD)-conjugated nanoliposomal formulations of asenapine maleate (ASP) for improvement in the transdermal delivery and pharmacokinetic profile of the drug. Novel arginine-terminated PDs (+/-lipidation) were prepared by solid phase peptide synthesis, followed by conjugation onto ASP nanoliposomes. The nanoliposomes were characterized for particle size (and polydispersity index), zeta potential (ZP), drug entrapment efficiency, shape and morphology, differential scanning calorimetry and FT-IR spectroscopy. Ex vivo skin permeation and retention studies demonstrated considerably higher percutaneous permeation of ASP from the developed nanoliposomes (Q24 = 794.31 ± 54.89 µg/cm2, Jss = 105.40 ± 4.8 µg/cm2/h, ER = 36.85 ± 2.89 for liposomes with lipidated peptide dendrimer (Lipo-PD2)) in comparison with passive diffusion studies (Q24 = 63.09 ± 3.56 µg/cm2, Jss = 3.01 ± 0.23 µg/cm2/h). Confocal Laser Scanning Microscopy (CLSM) confirmed the higher percutaneous penetration of Lipo-PD2 in comparison with liposomes without the dendrimer. In vitro cytotoxicity determined on HaCaT cell line demonstrated CTC50 of >1000 µg/mL for both the synthesized PDs and Lipo-PD2. Pharmacokinetic studies in male Sprague Dawley rats revealed considerably and significantly higher t1/2 = 82.32 ± 14.48 h and AUC0-t = 4403.34 ± 367.10 h.ng/mL, from the developed formulation, compared to orally administered ASP (t1/2 = 21.64 ± 2.53 h and AUC0-t = 2303.55 ± 444.5 h.ng/mL), demonstrating higher bioavailability and longer retention in vivo. Additionally, in vivo skin retention, brain uptake studies and pharmacodynamics of the developed formulations were investigated. Stability studies indicated that the formulations were stable up to relatively stable with respect to size, ZP and drug content for 4 months at the tested conditions. This study demonstrates that the developed PD-conjugated nanoliposomal formulations can effectively serve as a transdermal delivery strategy for ASP.

Long-term sustained release Poly(lactic-co-glycolic acid) microspheres of asenapine maleate with improved bioavailability for chronic neuropsychiatric diseases.

Schizophrenia and bipolar disorder are severe chronic neuropsychiatric diseases, affecting hundreds of millions of people worldwide. Asenapine maleate (ASM) has been demonstrated as a safe and effective therapeutic agent under twice-daily administration. However, lower compliance is observed when patients are treated with ASM, which significantly limits its application in schizophrenia and bipolar disorder. Moreover, the low bioavailability of ASM caused by first-pass metabolism and poor aqueous solubility also impairs the treatment effect. A formulation of ASM with the property of long-term sustained release and improved bioavailability can be a solution to overcome these weaknesses. In this article, we prepared ASM-loaded poly(lactic-co-glycolic acid) (ASM-PLGA) microspheres through different techniques, including emulsification-solvent evaporation (ESE), Shirasu porous glass membrane emulsification (SPG-ME), and microfluidic method. In vitro and in vivo assessments demonstrated that uniform-sized microspheres generated by the microfluidic process sustainably released ASM throughout 40-days, showing low burst release and significantly improved bioavailability. The results suggest that ASM-PLGA microspheres prepared by the microfluidic method provide an efficient strategy to enhance the drug exposure of ASM as the treatment of chronic neuropsychiatric diseases. It is also evident that this microfluidic strategy has the potential to construct with other drugs, establishing long-acting formulations.

Recent advances in the development of asenapine formulations.

INTRODUCTION: Asenapine maleate (AM) is an atypical antipsychotic agent, that has been widely prescribed for the management of schizoaffective disorders. However, the bioavailability of AM is extremely poor due to the extensive first-pass metabolism. With the advancement in pharmaceutical technologies, significant strides have been made to create novel formulations to address the bioavailability problem of AM. AREAS COVERED: This review article provides an insight into all the formulation approaches undertaken by researchers to increase the bioavailability of AM encompassing the works utilizing ultrasound mediated transdermal delivery, nose to brain delivery, intestinal lymphatic system targeting, in situ implants, etc. All the patents associated with AM formulation have also been discussed and summarized. EXPERT OPINION: Numerous studies have been carried out on AM formulations over the recent years, many of these studies have shown significant improvement in bioavailability. We have also mentioned the unexplored domains which can be exploited for further enhancing the bioavailability of AM. Nonetheless, most of these studies are still limited to the research laboratory level and face multiple hurdles before making into the market. Attaining controllability and reproducibility for the production of novel formulations is needed to enable its transition from bench to bedside.

Preparation, characterization, and optimization of asenapine maleate mucoadhesive nanoemulsion using Box-Behnken design: In vitro and in vivo studies for brain targeting.

The tight junctions between capillary endothelial cells of the blood-brain barrier (BBB) restricts the entry of therapeutics into the brain. Potential of the intranasal delivery tool has been explored in administering the therapeutics directly to the brain, thus bypassing BBB. The objective of this study was to develop and optimize an intranasal mucoadhesive nanoemulsion (MNE) of asenapine maleate (ASP) in order to enhance the nasomucosal adhesion and direct brain targetability for improved efficacy and safety. Box-Behnken statistical design was used to recognize the crucial formulation variables influencing droplet size, size distribution and surface charge of ASP-NE. ASP-MNE was obtained by incorporating GRAS mucoadhesive polymer, Carbopol 971 in the optimized NE. Optimized ASP-MNE displayed spherical morphology with a droplet size of 21.2 ± 0.15 nm and 0.355 polydispersity index. Improved ex-vivo permeation was observed in ASP-NE and ASP-MNE, compared to the ASP-solution. Finally, the optimized formulation was found to be safe in ex-vivo ciliotoxicity study on sheep nasal mucosa. The single-dose pharmacokinetic study in male Wistar rats revealed a significant increase in concentration of ASP in the brain upon intranasal administration of ASP-MNE, with a maximum of 284.33 ± 5.5 ng/mL. The time required to reach maximum brain concentration (1 h) was reduced compared to intravenous administration of ASP-NE (3 h). Furthermore, it has been established during the course of present study, that the brain targeting capability of ASP via intranasal administration had enhanced drug-targeting efficiency and drug-targeting potential. In the animal behavioral studies, no extrapyramidal symptoms were observed after intranasal administration of ASP-MNE, while good locomotor activity and hind-limb retraction test established its antipsychotic activity in treated animals. Thus, it can be concluded that the developed intranasal ASP-MNE could be used as an effective and safe tool for brain targeting of ASP in the treatment of psychotic disorders.

Screening of nanoemulsion components for asenapine maleate using validated RP-HPLC method.

A novel, simple reversed-phase high-performance liquid chromatographic (RP-HPLC) analytical method was developed and validated for the quantitative determination of asenapine from various nanoemulsion components during pre-formulation screening. The developed method was validated according to ICH Q2 (R1) guidelines. The developed and validated method was precisely and accurately quantified asenapine in various oils, surfactants and co-surfactants. The separation of asenapine was carried out on Hypersil BDS C18, 250×4.6mm, 5µm particle size column using methanol: acetonitrile (90:10) as mobile phase with a flow rate of 1mL.min-1. Measurement at 270nm for the concentration range of 5 to 50µg.mL-1 of the analyte was found to be linear with the determination coefficient (r2) of 0.999 as calculated by the least square regression method. The validated method was sensitive with LOD of 10.0ng.mL-1 and LOQ of 30.0ng.mL-1. Further, the method was precise and accurate, where the intraday and interday precision values were ranged from 0.70-0.95 and 0.36-0.95, respectively with the corresponding accuracy were ranged from 98.80-100.63 and 98.36-100.63. This developed and validated RP-HPLC method for asenapine was applied in the quantitative determination and screening of various oils, surfactants, and co-surfactants during the development of the asenapine maleate nanoemulsion.

One-pot reaction for determination of Asenapine maleate through facile complex formation with xanthine based dye: Application to content uniformity test.

Asenapine maleate was approved by the FDA for the treatment of schizophrenia and mania or mixed episodes with bipolar I disorder. In the present article, two spectroscopic methods were developed and validated for the determination of asenapine. Both methods depend on association complex formation between xanthine based dye (eosin Y) and the cited drug in acetate buffer pH = 3.8. In the spectrophotometric method (method I), the absorbance of the formed complex was estimated at maximum wavelength of 545 nm and Beer's law was obeyed in the range of 1-12 µg mL-1. The spectrofluorimetric method (method II) depends on measuring the quenching effect of the drug on the native fluorescence of eosin Y at 545 nm after excitation at 303 nm. The linearity range of method II was 0.4-3.2 µg mL-1. The limits of detection were 0.24 and 0.08 µg mL-1 for method I and II, respectively. The instructions of ICH were followed to fully validate the developed analytical procedures. The formation constant of the reaction was 3.93 × 104 while its Gibb's free energy was -2.6 × 104 J mol-1. Finally, the methods were applied for the analysis of pharmaceutical tablets and for evaluation of their content uniformity.

Surface engineered nanoliposomal platform for selective lymphatic uptake of asenapine maleate: In vitro and in vivo studies.

Asenapine maleate (ASPM) is an antipsychotic drug prescribed for the treatment of schizophrenia and bipolar disorder. ASPM possesses low oral bioavailability due to extensive hepatic metabolism. Therefore, RGD peptide conjugated liposomes loaded with ASPM were prepared to target Peyer's patches in the intestine which in-turn get access into intestinal lymphatic system thereby increasing the oral bioavailability of the drug. Liposomes were evaluated for size, zeta potential, differential scanning calorimetry (DSC), FTIR spectroscopy, X-ray diffraction (XRD), shape and morphology, in vitro drug release, cell line studies, everted intestinal uptake, pharmacodynamics, pharmacokinetics, tissue distribution, targetability and stability studies. In vitro drug release study showed the sustained release of drug from the formulations. Optimized liposomes (size <110 nm) showed greater permeability across the Caco2 + Raji B co-culture model in vitro and everted rat ileum ex vivo. Liposomes showed increase in bioavailability and high efficacy in reducing the L-DOPA-carbidopa induced locomotor count compared to plain drug. Liposomes also showed high concentration of drug in the brain after their oral administration. Imaging studies showed that RGD peptide conjugated liposomes were successful in targeting the Peyer's patches, both in vivo and ex vivo. The study successfully demonstrated the improved pharmacokinetics and efficacy profile of ASPM by using a ligand conjugated targeted liposomal system.

Asenapine maleate normalizes low frequency oscillatory deficits in a neurodevelopmental model of schizophrenia.

Asenapine maleate (AM) is an atypical antipsychotic that, unlike many other antipsychotics, shows some efficacy in treating cognitive dysfunction in schizophrenia. Normal cognitive function has long since been associated with high frequency neuronal oscillations. However, recent research has highlighted the potential importance of low frequency oscillations. Here, the impact of AM on low frequency neural oscillatory activity was evaluated in the methylazoxymethanol acetate (MAM) rat model system used for the study schizophrenia, and the oscillatory signatures compared to those of haloperidol (HAL) and clozapine (CLZ). AM and CLZ normalized low frequency spectral power deficits in the prefrontal cortex, while HAL and AM reversed corticostriatal and corticocortical delta coherence deficits. However, only chronic AM administration normalized corticostriatal and corticocortical delta coherence deficits between 3-4 Hz. These findings support the idea that antipsychotic-induced amelioration of both delta coherence and power may be important for therapeutic efficacy in treating the cognitive deficits inherent in schizophrenia.

Asenapine maleate-loaded nanostructured lipid carriers: optimization and in vitro, ex vivo and in vivo evaluations.

AIM: To prepare nanostructured lipid carriers (NLCs) loaded with asenapine maleate (ASPM) to increase its oral bioavailability by intestinal lymphatic uptake. MATERIALS & METHODS: ASPM-NLCs were prepared by ultrasound dispersion technique, by adopting Design of Experiment approach, and characterized. RESULTS: The optimized formulation exhibited good physicochemical parameters. Differential scanning calorimetry and x-ray diffraction studies indicated the amorphized nature of ASPM in lipid matrix. In vitro drug release study indicated the sustained release of drug from NLCs. ASPM-NLCs showed greater permeability across Caco2 cells and everted rat ileum. ASPM-NLCs showed greater cellular uptake, superior preclinical oral bioavailability and higher efficacy in reducing the L-DOPA-carbidopa-induced locomotor count compared with plain drug. CONCLUSION: ASPM-NLCs were successfully developed that showed enhanced performance both in vitro and in vivo.

Novel Drug Delivery Approach via Self-Microemulsifying Drug Delivery System for Enhancing Oral Bioavailability of Asenapine Maleate: Optimization, Characterization, Cell Uptake, and In Vivo Pharmacokinetic Studies.

Asenapine maleate (AM)-loaded self-microemulsifying drug delivery system (AM-SMEDDS) was prepared to increase its oral bioavailability. AM-SMEDDS was developed using Capryol 90, Cremophor EL, and Transcutol HP as oil, surfactant, and cosurfactant, respectively, by spontaneous emulsification method. Pseudoternary diagram showed maximum region at 3:1 ratio of Cremophor EL/Transcutol HP. The AM-SMEDDS showed globule size and zeta potential of 21.1 ± 1.2 nm and - 19.3 ± 1.8 mV, respectively. Globules were found to be of spherical shape and uniformly distributed by transmission electron microscopy. In vitro drug release study showed 99.2 ± 3.3% of drug release at the end of 8 h in phosphate buffer pH 6.8. Ex vivo drug release study showed only 15% of drug diffusion through stomach and ~ 85% drug was diffused through intestinal membrane. Confocal and flow cytometry study showed that cellular uptake of coumarin-6 loaded SMEDDS was significantly enhanced by Caco-2 cells as that of coumarin-6 solution. The relative bioavailability of AM-SMEDDS was found to be 23.53 times greater than AM suspension. Intestinal lymphatic transport study using Cycloheximide (CHX) showed that the AUCtotal of AM-SMEDDS reduced about 35.67% compared with that without the treatment of CHX indicating involvement of lymphatic system in intestinal absorption of AM-loaded SMEDDS. These findings demonstrated the potential of SMEDDS for oral bioavailability improvement of AM via lymphatic uptake. Graphical Abstract.

Enhanced intestinal absorption of asenapine maleate by fabricating solid lipid nanoparticles using TPGS: elucidation of transport mechanism, permeability across Caco-2 cell line and in vivo pharmacokinetic studies.

The aim of the present investigation was to fabricate and evaluate solid lipid nanoparticles (SLNs) of asenapine maleate (AM) to improve its oral bioavailability (BA). AM-SLNs were prepared by high speed homogenization followed by ultrasonication technique. The resultant SLNs exhibited particle size, zeta potential and entrapment efficiency of 114.3 ± 3.5 nm, -12.9 ± 3.8 mV, and 84.10% ± 2.90% respectively. In vitro release study of AM-SLNs showed 9.23% ± 2.72% and 92.09% ± 3.40% release of AM in pH 1.2 medium and phosphate buffer pH 6.8, respectively, indicating higher potential of lymphatic uptake. Cell viability study using Caco-2 cell line indicated non-toxicity of the carriers and drug. The uptake of AM-SLNs across Caco-2 cell line was time and energy dependent exhibiting clathrin-claveole mediated endocytosis transport. Cellular uptake of Coumarin loaded SLNs was effectively increased as compared to the dye solution. The pharmacokinetic results in rats showed 50.19-fold improvement in BA of AM after fabrication of SLNs. Collectively, all these findings demonstrated effectiveness of SLNs to improve therapeutic efficacy of AM in the treatment of schizophrenia.

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design, characterization, in vitro, ex vivo and in vivo appraisal.

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES4) were found to be 137.9 nm and -28.8 mV respectively. A maximum of 99.64 ± 0.16% of ASM was released from SES4 in 60 minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES4 showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the tmax determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55 ± 3.11% as extend of lymphatic absorption (r = 0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.

Preferential Formulation of Second Generation Antipsychotic Asenapine as Inclusion Complex with Sulphobutylether-ßCD (Captisol): In vitro and In vivo Evaluation.

BACKGROUND: Asenapine is an anti-psychotic agent approved by the US-FDA for treatment of acute schizophrenia and manic or bipolar I disorder in adults. It is poorly absorbed when administered orally, hence exhibits poor oral bioavailability, which limits its use in clinical practice. OBJECTIVE: Enhancement in solubility of asenapine through complexation with three different cyclodextrins, viz. ßCD, HPßCD and sulphobutylether-ßCD (Captisol®) was attempted and compared due to its poor bioavailability. METHOD: Kneading method was used for preparation of inclusion complexes which were characterized by FTIR, DSC, and XRD methods. Extent of binding and stability of the 1:1 inclusion complexes were evaluated by molecular modelling and phase solubility studies. Pharmacokinetic studies were also carried out of these inclusion complexes. RESULTS: Captisol® complex was the most stable amongst all complexes showing 4.9 times solubility enhancement of asenapine and 96% drug release at the end of 60 min, whereas asenapine maleate (uncomplexed drug) was released completely at the end of 120min. The Cmax and AUC values of Captisol® asenapine complex (AS-Captisol complex) were 2.8 and 2.3 times higher than the uncomplexed drug. CONCLUSION: This study thus demonstrated that Captisol® inclusion complex is an effective strategy for solubility and bioavailability enhancement of asenapine.

Preclinical pharmacokinetics and biodistribution studies of asenapine maleate using novel and sensitive RP-HPLC method.

AIM: Asenapine maleate (ASPM) is a newer antipsychotic drug available as a sublingual tablet in the market. EXPERIMENTAL: To investigate the pharmacokinetic and tissue distribution study of ASPM following oral administration in rats, reversed-phase HPLC method was developed and validated. RESULTS: ASPM was extracted from plasma and tissue matrix by liquid-liquid extraction technique and analyzed using mobile phase consisted of phosphate buffer pH 3.0 and acetonitrile (65:35% v/v). The method showed good linearity (10-500 ng/ml) with recovery 83-102%. In pharmacokinetics study, half-life was 32.74 ± 7.51 h due to slow elimination of drug. The biodistribution study indicated preferential distribution of ASPM to highly perfused organs. CONCLUSION: The current method can be successfully applied for estimating the drug in various biological matrices.

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability.

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl ß cyclodextrin inclusion complex (AM-HPßCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29-34 °c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120 min (99.1 ± 0.44%w/v). Dissolution in simulated nasal fluid was 92.33 ± 0.15%w/v at the end of 120 min. Locomotor activity was improved with nasal gel containing AM-HPßCD as compared to AM and AM-HPßCD oral solution in rats. Cmax for nasal gel was found to be more (9 ng/ml) as compared to AM-HPßCD (5.5 ng/mL) and oral standard solution (2 ng/ml). Tmax was found to be 1.5 h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.