Rivastigmine Hydrogen Tartrate Research Articles

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.

Convolvulus pluricaulis - Lipid hybrid nanoparticles to enhance in vivo exposure and uptake of rivastigmine for alzheimer disease

This study investigates Rivastigmine Hydrogen Tartrate (RHT)-loaded polymeric lipid hybrid nanoparticles (PLHNs) incorporating Shankhpushpi (Convolvulus Pluricaulis; C. Pluricaulis) extract. C. Pluricaulis was extracted using methanol, and PLHNs were formulated using a modified film hydration method with RHT, oleic acid, soy lecithin, Tween 80, PLA polymer, and Pluronic F-68. Characterization involved particle size, PDI, and zeta potential measurements using Dynamic Light Scattering (DLS), and morphology assessments via TEM and SEM. Drug-excipient interactions were analyzed using DSC and FTIR. In vitro release was evaluated using dialysis bags, and in vivo efficacy was tested in scopolamine-induced amnesic mice using the Morris Water Maze (MWM) test. The optimized formulation (NF6) demonstrated suitable particle size, PDI, zeta potential, encapsulation efficiency, and drug loading. NF6 significantly improved memory and exhibited antioxidant activity, indicating its potential for neurodegenerative disorder therapy.

Development and validation of high-performance liquid chromatography method for the simultaneous quantification of rivastigmine hydrogen tartrate and asiaticoside co-loaded in niosomes: A Box–Behnken design approach

Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, is considered as the first-line therapy for mild to moderate Alzheimer’s disease. Asiaticoside (AS), a pentacyclic triterpenoid saponin, is well known as cognitive enhancer due to its antioxidant effect. Based on the hypothesis of their synergistic therapeutic potential, RHT and AS were co-encapsulated in niosomal formulation. A simple, precise, and accurate high-performance liquid chromatography method was developed for simultaneous quantitative analysis. The chromatographic parameters were optimized by Box-Behnken experimental design. The separation was performed on a reversed-phase Phenomenex C18 (150 mm × 4.6 mm, 5 μm) column at 30 °C under the UV detection of 210 nm. The optimized mobile phase consisted of a mixture of 20 mM potassium dihydrogen phosphate buffer (pH 2.6) and acetonitrile (72:28 % v/v) under the isocratic mode at the flow rate of 0.9 mL/min. The developed method was fully validated under the ICH guidelines and could be successfully applied for simultaneous quantitative analysis of RHT and AS in niosomal formulation.

Development and Characterization of Rivastigmine Hydrogen Tartrate Elementary Osmotic Tablets

Development and Characterization of Rivastigmine Hydrogen Tartrate Elementary Osmotic Tablets

Rivastigmine-DHA ion-pair complex improved loading in hybrid nanoparticles for better amyloid inhibition and nose-to-brain targeting in Alzheimer’s

Rivastigmine hydrogen tartrate (RIV-HT) is given orally for Alzheimer's disease. However, oral therapy shows low brain bioavailability, short half-life and gastrointestinal-mediated adverse effects. RIV-HT intranasal delivery can avoid these side effects, but its low brain bioavailability remains challenging. These issues could be solved with hybrid lipid nanoparticles with enough drug loading to enhance RIV-HT brain bioavailability while avoiding oral route side effects. The RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) was prepared to improve drug loading into lipid-polymer hybrid (LPH) nanoparticles. Two types of LPH, i.e., cationic (RIV:DHA LPH(+ve)) and anionic LPH (RIV:DHA LPH(-ve)) were developed. The effect of LPH surface charge on in-vitro amyloid inhibition, in-vivo brain concentrations and nose-to-brain drug targeting efficiency were investigated. LPH nanoparticles showed concentration dependant amyloid inhibition. RIV:DHA LPH(+ve) demonstrated relatively enhanced Aβ1-42 peptide inhibition. The thermoresponsive gel embedded with LPH nanoparticles improved nasal drug retention. LPH nanoparticles gel significantly improved pharmacokinetic parameters compared to RIV-HT gel. RIV:DHA LPH(+ve) gel showed better brain concentrations than RIV:DHA LPH(-ve) gel. The histological examination of nasal mucosa treated with LPH nanoparticles gel showed that the delivery system was safe. In conclusion, the LPH nanoparticle gel was safe and efficient in improving the nose-to-brain targeting of RIV, which can potentially be utilized in managing Alzheimer's.

Quality-by-design driven analytical method (AQbD) development and validation of HPLC–UV technique to quantify rivastigmine hydrogen tartrate in lipidic nanocarriers: Forced degradation, and assessment of drug content and in vitro release studies

The main purpose of current investigation was to design and further validate a technique for the quantitative determination of rivastigmine hydrogen tartrate (RHT), a cholinesterase inhibitor in the nano formulations. With the employment of a reverse phase C18 column and a very simple mobile phase, an isocratic HPLC–UV analysis technique was developed, optimized, and validated following ICH Q2 (R1) requirements along with the inculcation ofAnalytical Quality-by-Design (AQbD) methodology. A two-level full factorial screening design was applied to filter out the variables influencing responses, followed by the application of central composite design (CCD) to further optimize the method using Design-Expert® software. Analyses were performed at room temperature with 0.9 mL. min−1 flow rate and detection wavelength of 215 nm. The optimized HPLC technique exhibited superior linearity, selectivity, and precision. The inherent stability of RHT was evaluated using the optimized method byconductingforced degradation studies. The RHT peak was clear and unaffected by matrix interference in the specimens from the forced degradation studies, drug content analysis, and in vitro release study. The assay had a limit of detection (LOD) of 14.32 ng. mL−1 and a limit of quantitation (LOQ) of 43.40 ng. mL−1. With acceptable intra- and interday precision, the methodologywas confirmedto berobust. The devised stability-indicating HPLC technique for analyzing RHT content, its stability in the nano formulations, and drug release in vitro proved to be selective, accurate, sensitive, and consistent.

The effect of single and repeated doses of rivastigmine on gastric myoelectric activity in experimental pigs.

Rivastigmine is a pseudo-irreversible cholinesterase inhibitor used for therapy of Alzheimer's disease and non-Alzheimer dementia syndromes. In humans, rivastigmine can cause significant gastrointestinal side effects that can limit its clinical use. The aim of this study was to assess the impact of rivastigmine on gastric motor function by means of electrogastrography (EGG) in experimental pigs. Six experimental adult female pigs (Sus scrofa f. domestica, hybrids of Czech White and Landrace breeds; 3-month-old; mean weight 30.7 ± 1.2 kg) were enrolled into the study twice and created two experimental groups. In group A, a single intragastric dose of 6 mg rivastigmine hydrogen tartate was administered in the morning to fasting pigs before EGG recording. In group B, rivastigmine was administered to overnight fasting animals in a dietary bolus in the morning for 7 days (6 mg per day). On day 8, an intragastric dose of 12 mg rivastigmine was given in the morning to fasting pigs before EGG. EGG recording was accomplished by means of an EGG standalone system. Recordings from both groups were evaluated in dominant frequency and EGG power (areas of amplitudes). In total, 1,980 one-minute EGG intervals were evaluated. In group A, basal EGG power (median 1290.5; interquartile range 736.5-2330 μV2) was significantly higher in comparison with the power of intervals T6 (882; 577-1375; p = 0.001) and T10 (992.5; 385-2859; p = 0.032). In group B, the dominant frequency increased significantly from basal values (1.97 ± 1.57 cycles per minute) to intervals T9 (3.26 ± 2.16; p < 0.001) and T10 (2.14 ± 1.16; p = 0.012), respectively. In group B, basal EGG power (median 1030.5; interquartile range 549-5093) was significantly higher in comparison with the power of intervals T7 (692.5; 434-1476; p = 0.002) and T8 (799; 435-1463 μV2; p = 0.004). Both single as well as repeated intragastric administration of rivastigmine hydrogen tartrate caused a significant decrease of EGG power (areas of amplitudes) in experimental pigs. EGG power may serve as an indirect indicator of gastric motor competence. These findings might provide a possible explanation of rivastigmine-associated dyspepsia in humans.

Transferrin functionalized nanostructured lipid carriers for targeting Rivastigmine and Resveratrol to Alzheimer's disease: Synthesis, in vitro characterization and brain uptake analysis

The management of Alzheimer's disease (AD) remains challenging owing to its complex pathophysiology and blood-brain barrier (BBB) restrictions. A rationally designed combination drug multi-target strategy has emerged as a promising approach for AD management. Considering the lipophilic nature of BBB and the need to embed dual drugs- Rivastigmine hydrogen tartrate and Resveratrol, nanostructured lipid carriers (NLCs) were used as drug delivery vehicle. NLCs were formulated by water/oil/water (w/o/w) double emulsion method and optimized using central composite design. HPLC method for simultaneous determination of drugs was developed and validated. To target the overexpressed Transferrin (TF) receptors, NLCs were surface functionalized with TF by covalent coupling employing carbodiimide chemistry. The success of conjugation was ascertained by Zeta potential, FTIR and TEM and the Bradford assay which estimated the conjugation efficiency of 47.52 ± 3.2%. A particle size of <100 nm was obtained which is favourable for brain delivery. Sustained release of drugs from nanoparticles was obtained, where TF-NLCs demonstrated a significantly slow release compared to NLCs. The functional stability and biocompatibility of the nanosystems was ensured by DPPH assay and hemolysis test, respectively. The confocal laser scanning microscopy (CLSM) revealed significantly higher (∼1.7 folds) brain uptake of TF-NLCs compared to NLCs in vivo following intraperitoneal administration. Dual drugs loaded TF functionalized NLCs demonstrated favourable in vitro and in vivo attributes for efficient brain targeting and hence AD management.

Sensitive RP-HPLC method of rivastigmine for applicative quantification of nanostructured lipid carriers

The present research work focuses on development of a rapid, simple, precise, accurate and robust RP-HPLC method for quantitative estimation of rivastigmine hydrogen tartrate (RIV-HT) in bulk and formulations. Systematic optimization of the method observed two critical parameters, viz. pH of mobile phase and mobile phase ratio that particularly affected peak area, tailing factor and number of theoretical plates. The optimized mobile phase consisted of ACN (0.05 % v/v triethylamine): 10 mM, pH 5.5 phosphate buffer: IPA (33:65:2 v/v). The limit of detection and limit of quantification values were observed to be 7.32 and 24.15 ng/mL, with a linearity range between 25-600 ng/mL. The proposed method was observed to be specific in presence of solution and solid-state stress conditions. It was also specific in the presence of formulation excipients, release and permeation medium. The method was applied to estimate encapsulation efficiency, in-vitro release profiles, and ex-vivo nasal permeation efficiency of RIV-HT loaded nanostructured lipid carriers. The obtained results advocate that the newly proposed method is sensitive compared to the previously published reports and can be explicitly utilized for estimating RIV-HT in bulk and nanoformulations.

Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease.

The present study aimed to examine the effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease (AD). For this purpose, a total of 126 patients with AD admitted to Luoyang Central Hospital from January, 2018 to December, 2018 were enrolled. Patients were divided into different groups according to the treatment they selected. Patients treated with single-agent donepezil were separated into a monotherapy group (n=56), and patients receiving donepezil plus rivastigmine were placed in the combination group (n=70). Before and after treatment, the cognitive functions, mental behavior and quality of life of the patients in the two groups were respectively evaluated by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Blessed-Roth Dementia Scale (BRDS) and the QOL-AD. In addition, the serum bradykinin level was detected by enzyme-linked immunosorbent assay. Following treatment, the MMSE score, BRDS, ADAS-Cog and QOL-AD scores were improved compared with those before treatment (P<0.05). However, following treatment, the 4 scores in the combination group were significantly higher than those in the monotherapy group (P<0.05). No significant differences were observed in the incidence of adverse reactions between the 2 groups (P>0.05). Following treatment, the bradykinin level in both groups was significantly decreased (P<0.05), although the decrease in the combination group was more significant than that in the monotherapy group (P<0.05). On the whole, the findings of the present study indicate that rivastigmine hydrogen tartrate used in combination with donepezil hydrochloride relieves the symptoms and improves the quality of life of patients with AD more effectively, which may be related to the reduction of the bradykinin level in these patients.

Biodistribution and amyloid beta induced cell line toxicity study of intranasal Rivastigmine microemulsion enriched with Fish Oil and Butter oil

Aim of the current study was to evaluate the biodistribution of Butter oil (BO), and Fish oil (FO) loaded Rivastigmine hydrogen tartrate (RHT) microemulsion in blood and brain via intranasal route (IN). For that, binary mixtures of RHT BO and RHT FO (in the ratio of 1:9 to 9:1) were prepared by simple physical mixing and optimized by in-vitro diffusion study. The ratio of a binary mixture which gave higher diffusion of RHT was selected and added in ME for the development of RHT BO ME and RHT FO ME. The developed formulation exhibited lower globule size (65.76 ± 5.23 nm and 69.72 ± 7.85 nm) and PDI (0.180 ± 0.029 and 0.290 ± 0.010) respectively. In-vitro cytotoxicity study revealed safety of formulation for delivery via IN route. Higher bioavailability and Direct Targeting potential value was observed with RHT FO ME and RHT BO ME in comparison to RHT ME via IN route, suggesting that BO and FO enhanced the diffusion of RHT across nasal olfactory membrane to brain.

Formulation and Evaluation of Eudragit RL-100 Nanoparticles Loaded In-Situ Forming Gel for Intranasal Delivery of Rivastigmine.

Purpose: Rivastigmine hydrogen tartrate (RHT) is commonly used for the treatment of mild to moderate Alzheimer’s disease (AD). The aim of this work was to formulate in-situ pluronic F-127 (PF-127) hydrogels containing Eudragit RL-100 (EU-RL) nanoparticles (NPs) in order to improve the therapeutic efficacy of RHT through the nasal route. Methods: The NPs were prepared using different polymer to drug ratios and evaluated for their physicochemical characteristics, cellular uptake and in vitro cytotoxicity against lung adenocarcinoma cells (A459). PF-127 nanoformulations were prepared via cold method and analyzed in terms of physicochemical properties and drug release profiles. The nanoformulations and plain drug gel were then assessed by ex vivo permeation studies across the sheep nasal mucosa. Results: The EU-RL NPs exhibited a particle size within the range of 118 to 154 nm and positive zeta potential values of 22.5 to 30 mV with an approximately spherical shape. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) suggested no drug to polymer interaction through the preparation of nanoformulations. The RHT-loaded NPs exhibited an acceptable cytocompatibility with a time- and dose-dependent cellular internalization.Conclusion: Our results clearly indicated the potential of nanoformulations as controlled release systems to improve the therapeutic efficacy of RHT through the intranasal administration

Electrochemical Determination of Rivastigmine Hydrogen Tartrate at β-Cyclodextrin/Multi-Walled Carbon Nanotubes Modified Electrode

Background: Electrochemical techniques can easily be adopted to solve many problems of pharmaceutical interest. The implementation of electroanalytical methods in the assay of pharmaceutical formulations has increased greatly. Nowadays, owing to the critical importance of electron transfer and surface properties, chemically modified electrodes have been employed in electrochemical sensors. The chemically modified electrode is one of the most popular electroanalytical sensors and used in several applications. Methods: In this work, a β-cyclodextrine/multi-walled carbon nanotubes (β-CD/MWCNTs) composite modified glassy carbon electrode (GCE) was produced and applied to the detection of Rivastigmine hydrogen tartrate (RVT) in pharmaceutical formulations. The voltammetric feature of RVT at this β- CD/MWCNTs modified electrode was evaluated using cyclic voltammetry and square wave voltammetry. Results: The β-cyclodextrin and multi-walled carbon nanotubes modified glassy carbon electrode displayed good electrocatalytic activity in the oxidation of rivastigmine hydrogen tartrate with relatively high sensitivity, stability and lifetime. The calibration graph of the analyte was linear over the range 10- 1500 µM with two linear segments and the detection limit was obtained as 2.0 µM (S/N=3). The results showed that the electrochemical sensor has good sensitivity and selectivity. Conclusion: The β-CD/MWCNTs modified electrode displayed a high electrochemical activity and good sensitivity toward the oxidation of RVT. Compared with the bare MWCNTs coated sensor, the response of analyte increased soundly and the response potential of target analyte shifted negatively. The results indicated that the β-CD/MWCNTs film coated electrode had good catalysis to the voltammetric oxidation of RVT. The prepared sensor was applied to determine RVT in pharmaceutical samples with satisfactory yields. The outcomes indicate that β-CD/MWCNTs coated electrode is a safe choice for the detection of RVT.

PLACKETT–BURMAN DESIGN AS A TOOL FOR SCREENING AND PROCESS OPTIMIZATION OF RIVASTIGMINE-LOADED LIPID NANOCARRIERS

Objective: Plackett–Burman experimental design is used to identify the most important factors early in the experimentation phase when complete knowledge about the system is usually unavailable. The objective of this study was to screen out the most important factors affecting the size and entrapment efficiency of rivastigmine hydrogen tartrate (RHT) nanostructured lipid carriers (NLCs).Methods: The RHT-loaded NLC was prepared by the modified solvent emulsification-diffusion method. The independent variables selected for Plackett–Burman design were drug: lipid ratio, solid lipid/liquid lipid (S/L) ratio, concentration Ryoto sugar ester (%w/v), the concentration of poloxamer 188 (%w/v), sonication time (min), sonication amplitude, and stirring time (h).Results: The R2 value for the particle size equation was 86.16%. p value was (&lt;0.05) 0.048 in case of sonication time. In case of entrapment efficiency, the R2 value was 87.12%. The p value (p&lt;0.05) for S/L ratio and the Ryoto sugar (% w/v) was 0.028 and 0.042, respectively.Conclusion: It can be concluded that sonication time has a significant effect on particle size, whereas S/L ratio and Ryoto sugar ester concentration have a significant effect on entrapment efficiency.

An Alternative Approach for Improved Entrapment Efficiency of Hydrophilic Drug Substance in PLGA Nanoparticles by Interfacial Polymer Deposition Following Solvent Displacement

Background: Alzheimer’s disease (AD) is an age-related and irreversible neurological disorder. The low efficacy of current therapeutic strategies is related to both poor drug potency and the presence of various obstacles in the delivery routes, such as blood-brain barrier (BBB) that limits the uptake of most drugs by the brain. Rivastigmine hydrogen tartrate (RHT) is used in mild to moderate forms of AD therapy. Objectives: The present study described the use of Poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs), as effective delivery vehicles, to improve the therapeutic efficiency of RHT. Methods: RHT-loaded PLGA NPs were prepared using interfacial polymer deposition, following solvent displacement method with different ratios of polymer: Drug. The NPs were studied for entrapment efficiency, particle size, and surface morphology, using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro drug release from NPs was also assessed by a modified dissolution method. Results: The entrapment efficiency of RHT in NPs was found to be between 27.71 ± 6.86 and 45.70 ± 11.06 and the average size was about 75.14 to 173 nm. The zeta potential was negative (-2.28 to -10.5 mV), as determined by dynamic light scattering (DLS). The drug released from NP formulations was between 69.98% and 89% upon 24 hours, which indicated improved sustained drug release characteristics. Conclusions: These results suggested the potential usefulness of PLGA NPs for the delivery of RHT in a sustained and controlled manner.

Sucrose stearate as a biosurfactant for development of rivastigmine containing nanostructured lipid carriers and assessment of its activity against dementia in C. elegans model

Dementia defines wide-ranging symptoms related to a decline in memory or coherent thinking. The focused endeavor of the present study was to develop and assess the efficacy of rivastigmine hydrogen tartrate (RHT) loaded nanostructured lipid carrier (RHT-NLCs) for the cure of dementia. The rise of dementia cases necessitates a curative therapy which is safe as well as effective. RHT-NLCs were developed by a modified solvent emulsification-diffusion method. Box-Behnken design was used for optimization of the developed formulation. The particle size, polydispersity index, zeta potential and percent entrapment efficiency of the optimized RHT-NLCs formulation was found to be 266 ± 0.94 nm, 0.233, −16.58 mV and 61.82 ± 2.52% respectively. RHT-NLCs displayed 81.23 ± 2.14% drug diffusion in 12 h through goat nasal mucosa and aldicarb assay exhibited increased worm paralysis due to increased concentration of acetylcholine in C. elegans model. Quantitative RT-PCR of RHT-NLCs displayed acetylcholinesterase expressing enzymes (AChE 1 and AChE 2) down-regulation, responsible for the expression of acetylcholinesterase by 4.92 ± 0.06 and 5.42 ± 0.33 respectively. Significant improvement was found in escape latency and transfer latency after treatment with RHT-NLCs in a rat model. Above results point towards the treatment/cure of dementia through RHT-NLCs developed using Compritol 888 ATO, Ryoto Sugar ester and Triacetin.

MCM-41 Nanoparticles for Brain Delivery: Better Choline-Esterase and Amyloid Formation Inhibition with Improved Kinetics

The present study was aimed at delivering a low bioavailability drug, rivastigmine hydrogen tartrate (RTG), to the brain through its encapsulation in mesoporous silica nanoparticles (MSNs) and targeted to amyloid inhibition in the brain. MSNs were characterized for size, zeta potential, and drug entrapment using SEM, TEM, HR-TEM, FT-IR, and PXRD. Drug-loaded MSNs were assessed for in vitro release kinetics and ex vivo followed by animal studies. The average size of the prepared blank (MCM-41B) and drug-loaded MSNs (MCM-41L) was 114 ± 2.0 and 145 ± 0.4 nm with the zeta potential of approximately -43.5 ± 1.1 and -37.6 ± 1.4 mV, respectively. MCM-41L exhibited an average entrapment efficiency of 88%. In vitro release studies exhibited early surge followed by a sluggish persistent or constant release (biphasic pattern). Hemolytic studies proved that the developed MCM-41L NPs are less hemolytic compared to RTG. A reduced ThT fluorescence was observed with MCM-41L compared to MCM-41B and RTG in the amyloid inhibition studies. A significant (p < 0.05) inhibition of AChE (acetycholinesterase) was observed for MCM-41L (80 ± 4.98%), RTG (62 ± 3.25%), and MCM-41B (54 ± 4.25%). In vivo pharmacokinetics in Wistar rats revealed that the AUC and mean residence time (MRT) for MCM-41L was sustained and significantly higher (p < 0.05) (780 ± 3.30 ng/L; 5.49 ± 0.25 h) compared to RTG solution (430 ± 3.50 ng/L; 0.768 ± 0.17 h). Similarly, the half-life was found to be significantly higher in case of MCM-41L. The promising result was brain delivery of RTG in Wistar rats which was enhanced almost 127 folds in vivo, using MCM-41L nanoparticles. MCM-41L nanoparticles effectively enhanced the bioavailability of RTG. Conclusively, these can be used for the administration of RTG and other related low bioavailability drugs for improved brain delivery.

Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting.

Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics. ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies). The developed ME and MME were transparent having globule size approximately in the range of 53-55nm. Pharmacokinetic studies showed higher values for Cmax and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT. Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.

A Stability Indicating HPLC Assay Method for Analysis of Rivastigmine Hydrogen Tartrate in Dual-Ligand Nanoparticle Formulation Matrices and Cell Transport Medium.

The objective of this study was to develop and validate a method for quantitative analysis of rivastigmine hydrogen tartrate (RHT) in dual-ligand polymeric nanoparticle formulation matrices, drug release medium, and cellular transport medium. An isocratic HPLC analysis method using a reverse phase C18 column and a simple mobile phase without buffer was developed, optimised, and fully validated. Analyses were carried out at a flow rate of 1.5 mL/min at 50°C and monitored at 214 nm. This HPLC method exhibited good linearity, accuracy, and selectivity. The recovery (accuracy) of RHT from all matrices was greater than 99.2%. The RHT peak detected in the samples of a forced degradation study, drug loading study, release study, and cellular transport study was pure and free of matrix interference. The limit of detection (LOD) and limit of quantification (LOQ) of the assay were 60 ng/mL and 201 ng/mL, respectively. The method was rugged with good intra- and interday precision. This stability indicating HPLC method was selective, accurate, and precise for analysing RHT loading and its stability in nanoparticle formulation, RHT release, and cell transport medium.

Thermosensitive in situ nanocomposite of rivastigmine hydrogen tartrate as an intranasal delivery system: Development, characterization, ex vivo permeation and cellular studies

Intranasal administration of pharmaceutical compounds is gaining considerable attention as an alternative route for localized/systemic drug delivery. However, insufficient therapeutic efficacy of drugs via this route seems to be a major challenge for development of de novo intranasal formulations. This shortcoming can be overcome by simultaneous utilization of a nanoparticulate delivery system with a polymeric gel network. Therefore, the main aim of the present study was to develop erodible in-situ gel forming systems of poloxamer 407® (P407) as a promising platform, capable of prolonging rivastigmine hydrogen tartrate (RHT) release from the embedded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). PLGA NPs containing RHT were formulated and characterized, then were embedded in P407 gel forming matrix and analyzed in terms of viscosity, stability, gelation temperature, loading efficiency and mucoahesive behavior. The cytotoxicity of NPs was evaluated on A549 cell line using MTT assay. Cellular uptake of the NPs was also measured by means of fluorescence microcopy and flow cytometry analyses. The formulations were finally evaluated for their permeability across sheep nasal mucosa. A linear dependence of sol-gel temperature (Tsol-gel) on the P407 concentration was observed, and a P407 content of 18% was selected. The loading efficiencies of formulations were found to be around 100.22–104.31%. The RHT-loaded NPs showed a suitable cytocompatibility on A549 cells with a time-dependent increase in cellular uptake. Besides, nanocomposites showed higher amounts of drug permeation through nasal sheep mucosa than plain drug gel. Taken all, it is concluded that the formulated nanocomposites may be considered as useful drug delivery systems for the nasal delivery of RHT with enhanced therapeutic efficacy.