Bioavailability Study of a Transdermal Patch Formulation of Rivastigmine Compared with Exelon in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Rivastigmine is a reversible cholinesterase inhibitor indicated for the treatment of all stages of Alzheimer's disease (AD). Transdermal patch formulation allows smooth and continuous drug delivery. Its tolerability, efficacy and convenience of use increase treatment compliance. This study was designed to evaluate the bioavailability and to assess the bioequivalence of two rivastigmine transdermal patches at steady state (RIV-TDS Test Product versus Exelon Marketed Reference Product), with a release rate of 13.3 mg/24 h, after multiple patch applications. As secondary objectives, safety, patch adhesion and skin irritation were evaluated. METHODS: This was an open-label, randomized, balanced, two-period, two-sequence, cross-over study of healthy adults (n = 31). The treatment period consisted of two 5-day study periods during which consecutive daily application of the investigational patches with a release rate of 13.3 mg/24 h rivastigmine took place. Serial blood samples were collected to measure plasma concentrations. Adhesion and skin irritation assessments were performed after application of patches. RESULTS: Point estimates and 90% confidence intervals of pharmacokinetic parameters at steady state, viz. area under the plasma concentration versus time curve from dosing time to the end of the dosing interval τ (profile day) at steady state [AUC0-τ,ss] (97.4; 88.8-106.9), maximum plasma concentration within the dosing interval τ (profile day) at steady state [Cmax,ss] (99.6; 90.4-109.7) and trough plasma concentration at the end of the dosing interval τ (profile day) at steady state [Cτ,ss] (96.8; 86.2-108.9), demonstrated that both patches were bioequivalent. Evaluation of patch adhesion showed better skin adherence for RIV-TDS as well as dermal response scores (skin tolerability after removal). CONCLUSIONS: For both products, bioequivalence was shown and systemic tolerability was in accordance with the safety profile of the drug substance. The trial is registered in ClinicalTrials.gov: NCT03573050 and EudraCT: 2018-000968-28.

Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer's disease.

With the increasing aging population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of ß-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.

Systematic development of lectin conjugated microspheres for nose-to-brain delivery of rivastigmine for the treatment of Alzheimer's disease.

The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment.

Design, development and in-vitro/in-vivo evaluation of intranasally delivered Rivastigmine and N-Acetyl Cysteine loaded bifunctional niosomes for applications in combinative treatment of Alzheimer's disease.

The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7% for RIV and 85.9% for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4-8 °C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.

Bioinspired lipid-polysaccharide modified hybrid nanoparticles as a brain-targeted highly loaded carrier for a hydrophilic drug.

Lipid-polysaccharide modified biohybrid nanoparticles (NPs) are eminent drug carriers for brain targeting, owing to their ability to prolong the circulation time and penetrate the blood brain barrier (BBB). Biohybrid NPs particular interest arises from their potential to mimic biological components. Herein, we prepared bioinspired lipid polymeric NPs, either naked or surface modified by a synthesized biocompatible dextran-cholic acid (DxC). The nanoprecipitation method was tailored to allow the assembly of the multicomponent NPs in a single step. Modulating the solvent/antisolvent system provided lipid polymer hybrid NPs in the size of 111.6 ± 11.4 nm size. The NPs encapsulated up to 92 ± 1.2% of a hydrophilic anti-Alzheimer drug, rivastigmine (Riv). The brain uptake, biodistribution and pharmacokinetics studies, proved the efficient fast penetration of the bioinspired surface modified NPs to the brain of healthy albino rats. The modified nanocarrier caused a 5.4 fold increase in brain targeting efficiency compared to the drug solution. Furthermore, the presence of DxC increased Riv's brain residence time up to 40 h. The achieved results suggest that the fabricated biohybrid delivery system was able to circumvent the BBB and is expected to minimize Riv systemic side effects.

Gel-based Microemulsion Design and Evaluation for Topical Application of Rivastigmine.

OBJECTIVE: The aim of the present study was to design nanocarriers for the topical application of rivastigmine. METHODS: The effect of cosurfactants, hydrophilic gel and loading amount on the permeability of rivastigmine through rat skin was evaluated. Skin irritation tests and stability tests were performed to evaluate the utility of tested formulations. RESULTS: The results showed that the microemulsion formation and characteristics of drug-loaded formulations were related to many parameters of the components. When using microemulsion systems as a vehicle, the permeation rate remarkably increased about 13.2~24.3-fold and the lag time was significantly shortened from 24 h to 4.7 h. Formulations containing a cosurfactant of Diethylene Glycol Monobutyl Ether (DEGBE) showed higher enhancement effect, while increasing the loading dose from 0.5% to 5% further increased the flux about 2.1-fold and shortened the lag time. CONCLUSION: The drug-loaded experimental formulation did not cause skin irritation and had good stability at 20ºC and 40ºC storage for at least 3 months. The result showed that gel-based microemulsion formulation could be a promising approach for topical administration.

Optimization and characterization of rivastigmine nanolipid carrier loaded transdermal patches for the treatment of dementia.

The present study aimed to develop nanolipid carrier (NLC) loaded transdermal system of rivastigmine for bioavailability enhancement. NLC was optimized using Box-Behnken Design (BBD). Optimized formulation comprises oil (4% w/w), tween 80 (3% w/w) and span 80 (1.8% w/w) and was characterized. It was found that the formulation exhibit 134.60 ±â€¯15.10 nm, 0.286 ±â€¯0.041, -11.80 ±â€¯2.24 mV and 70.56 ±â€¯1.20% of mean size, polydispersity index (PDI), zeta potential and entrapment efficiency, respectively. In vitro release studies showed there was more sustained release of drug from NLC loaded transdermal patches in comparison to Exelon® patch. Skin irritation studies proved the non-irritant nature of developed NLC based transdermal patch. From pharmacokinetic studies it was observed that there was increased Cmax and AUC0-72 in plasma treated with NLC loaded transdermal patches as compared to conventional patch. These experimental results indicate that NLC based transdermal patch could be utilized as a potential carrier for enhancing bioavailability of rivastigmine for the better treatment and management of dementia.

Sex-by-formulation interaction in bioequivalence trials with transdermal patches.

PURPOSE: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males may not be representative of the results obtained in females and vice versa. The best evidence of the existence of a sex-by-formulation interaction has been obtained from a study conducted with transdermal patches. This observation might be caused by the different characteristics of the skin of males and females. The purpose of this work is to investigate the existence of a sex-by-formulation interaction in all bioequivalence studies of transdermal patches submitted to the Spanish Agency for Medicines between 2010 and 2016. METHODS: Only five different products (Buprenorphine-1, Fentantyl-1, Fentanyl-2, Rivastigmine-1 and Rivastigmine-2) that were submitted for registration included nine bioequivalence studies conducted in males and females. As single dose and multiple dose studies are required for registration of transdermal patches in the European Union, more than one study may be available to confirm the existence of a sex-by-formulation interaction. RESULTS: A sex-by-formulation interaction is suggested in six out of 27 datasets (22%), corresponding to two products, and it is statistically significant in three of them (11%). CONCLUSIONS: The sex-by-formulation interaction detected in some pharmacokinetic parameters of some studies is excluded when the study is repeated, which shows that these results are not reproducible. There is no evidence to require bioequivalence demonstration for transdermal patches in males and females separately.

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

PURPOSE: 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. METHODS: 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). RESULTS: The developed ME and MME were transparent having globule size approximately in the range of 53-55 nm. 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. CONCLUSION: 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.

Intervenciones farmacológicas que mejoren la cognición y el funcionamiento adaptativo en el síndrome de Down: Progresos hasta la fecha / No disponible

Pese al creciente número de ensayos clínicos desarrollados para evaluar la cognición en el síndrome de Down, sus resultados para identificar intervenciones eficaces han sido muy limitados hasta la fecha. Las intervenciones en los modelos animales, con frecuencia muy favorables, no se han visto reflejadas en los ensayos clínicos. Esta revisión describe los resultados de los principales ensayos realizados. Ofrece consideraciones a los investigadores y describe estrategias a la industria farmacéutica para que se implique crecientemente en el descubrimiento de fármacos en el síndrome de Down

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers.

OBJECTIVE: To assess the bioequivalence of generic formulation of rivastigmine (test) and Exelon (reference). METHODS: This randomized, open-label, 2-period, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 40 healthy men under fed condition. Participants were randomized to receive a single dose of Exelon or rivastigmine capsule. RESULTS: A total of 31 participants completed the study. Area under the concentration-time curve from time zero to time t (AUC0- t) and area under the concentration-time curve from time zero to infinity (AUC0-∞) for Exelon (mean [standard deviation], h·ng/mL) were 126.40 (56.95) and 129.46 (59.94), respectively, while they were 122.73 (43.46) and 125.08 (45.39) for rivastigmine. Geometric mean ratios of rivastigmine/Exelon were 99.17% for AUC0- t, 98.81% for AUC0-∞, and 105% for maximum observed plasma concentration ( Cmax). The 90% confidence intervals (CIs) were 94.14% to 104.46%, 93.77% to 104.12%, and 93.08% to 118.44%, respectively. Both formulations were well tolerated. CONCLUSION: The generic and reference formulations were bioequivalent, as the 90% CIs for Cmax, AUC0- t, and AUC0-∞ were within the range of 80% to 125%.

Factors affecting therapeutic response to Rivastigmine in Alzheimer's disease patients in Taiwan.

Rivastigmine has been widely used in mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A dose-dependent effect has been suggested, but the plasma concentration of rivastigmine and its metabolite, NAP 226-90, were not measured in previous studies. The influencing factors of therapeutic response are complicated and discordant in various studies among different ethnic groups. Hence, we analyzed the therapeutic responses of rivastigmine, measured by neuropsychological assessments, among 63 clinically diagnosed AD patients taking a daily dosage of 6-9 mg in relation to their plasma concentration of rivastigmine and NAP 226-90, apolipoprotein E (APOE) genotype and demographic characteristics. Our reports revealed that 41.3% of recruited AD patients had improvement in cognition, measured by Mini-Mental Status Examination (MMSE), and 63.5% in global status, by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. In cognition, the clinically improving group had a significantly higher rivastigmine concentration [p = 0.049, odds ratio (OR) = 1.029, 95%CI = 1.000-1.058], lower initial MMSE score (p = 0.010, OR = 0.708, 95%CI = 0.546-0.920), and lower initial CDR-SB score (p = 0.003, OR = 0.552, 95%CI = 0.372-0.817). The patients with APOE ε4 allele had worsening cognition (p = 0.037, OR = 3.870, 95%CI = 1.082-13.840). In global status, only higher education (p = 0.043, OR = 1.222, 95%CI = 1.007-1.484) was significantly associated with clinical improvement. In conclusion, high concentrations of rivastigmine may benefit cognitive function of AD patients, especially in APOE ε4 (-) carriers.

Enhancement of oral bioavailability of rivastigmine with quercetin nanoparticles by inhibiting CYP3A4 and esterases.

BACKGROUND: Quercetin is a well-known flavonoid, has pharmacokinetic interaction with ester drugs due to its capability of esterase inhibition in the gut and liver. However, the interaction between quercetin nanoparticles (NQC) and rivastigmine has not been reported. Hence, the present study was performed to evaluate the effect of quercetin alone and its nanoparticles on the pharmacokinetics of rivastigmine in rats. METHODS: NQC prepared by antisolvent precipitation method. The influence of quercetin on the pharmacokinetics of rivastigmine was evaluated by following methods i.e. in vitro inhibitory effect on esterase enzyme in rat liver microsomes and in vitro assessment of CYP3A activity using erythromycin-N-demethylase (EMD) assay. To confirm these findings, an in vivo pharmacokinetic study of orally administered rivastigmine in rats with quercetin and NQC pretreatments was performed. RESULTS: The size of NQC was observed below 300nm. Quercetin significantly (p<0.05) inhibited the esterase-mediated metabolism of rivastigmine. In in vitro assessment of CYP3A activity model the erythromycin-N-demethylation (EMD) levels in quercetin treated group were significantly reduced (p<0.05). Cmax, AUC0-t and AUC0- ∞ of rivastigmine were found to be increased in quercetin and NQC pretreated groups. Further, the CL/F and Vd/F of rivastigmine were significantly decreased. CONCLUSIONS: The results revealed that enhanced bioavailability of rivastigmine might be caused by the combination of their effects due to CYP3A and esterase inhibition, Therefore, concomitant administration of NQC influences the bioavailability of rivastigmine and also has synergetic effect in the treatment of Alzheimer's disease.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals.

AIMS: To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. METHODS: A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58-75 years. RESULTS: Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml-1 . The NAP226-90 to rivastigmine AUC0-∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose. An estimated dose of two or three sprays twice-daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6-9.7 mg day-1 oral dose and a 10 cm2 transdermal patch, respectively. CONCLUSIONS: The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226-90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice-daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples.

Pharmacokinetic Modeling to Simulate the Concentration-Time Profiles After Dermal Application of Rivastigmine Patch.

Rivastigmine is an inhibitor of acetylcholinesterases and butyrylcholinesterases for symptomatic treatment of Alzheimer disease and is available as oral and transdermal patch formulations. A dermal absorption pharmacokinetic (PK) model was developed to simulate the plasma concentration-time profile of rivastigmine to answer questions relative to the efficacy and safety risks after misuse of the patch (e.g., longer application than 24 h, multiple patches applied at the same time, and so forth). The model comprised 2 compartments which was a combination of mechanistic dermal absorption model and a basic 1-compartment model. The initial values for the model were determined based on the physicochemical characteristics of rivastigmine and PK parameters after intravenous administration. The model was fitted to the clinical PK profiles after single application of rivastigmine patch to obtain model parameters. The final model was validated by confirming that the simulated concentration-time curves and PK parameters (Cmax and area under the drug plasma concentration-time curve) conformed to the observed values and then was used to simulate the PK profiles of rivastigmine. This work demonstrated that the mechanistic dermal PK model fitted the clinical data well and was able to simulate the PK profile after patch misuse.

Efficacy of rivastigmine tartrate, transdermal system, in Alzheimer's disease.

INTRODUCTION: As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD. AREAS COVERED: This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD. EXPERT OPINION: The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.

Role of P-glycoprotein in mediating rivastigmine effect on amyloid-ß brain load and related pathology in Alzheimer's disease mouse model.

Recently, we showed that rivastigmine decreased amyloid-ß (Aß) brain load in aged rats by enhancing its clearance across the blood-brain barrier (BBB) via upregulation of P-glycoprotein (P-gp) and low-density lipoprotein receptor-related protein 1 (LRP1). Here, we extend our previous work to clarify P-gp role in mediating rivastigmine effect on Aß brain levels and neuroprotection in a mouse model of Alzheimer's disease (AD) that expresses different levels of P-gp. APPSWE mice were bred with mdr1a/b knockout mice to produce littermates that were divided into three groups; APP(+)/mdr1(+/+), APP(+)/mdr1(+/-) and APP(+)/mdr1(-/-). Animals received rivastigmine treatment (0.3mg/kg/day) or vehicle for 8weeks using Alzet osmotic mini-pumps. ELISA analysis of brain homogenates for Aß showed rivastigmine treatment to significantly decrease Aß brain load in APP(+)/mdr1(+/+) by 25% and in APP(+)/mdr1(+/-) mice by 21% compared to their vehicle treated littermates, but not in APP(+)/mdr1(-/-) mice. In addition, rivastigmine reduced GFAP immunostaining of astrocytes by 50% and IL-1ß brain level by 43% in APP(+)/mdr1(+/+) mice, however its effect was less pronounced in P-gp knockout mice. Moreover, rivastigmine demonstrated a P-gp expression dependent neuroprotective effect that was highest in APP(+)/mdr1(+/+)>APP(+)/mdr1(+/-)>APP(+)/mdr1(-/-) as determined by expression of synaptic markers PSD-95 and SNAP-25 using Western blot analysis. Collectively, our results suggest that P-gp plays important role in mediating rivastigmine non-cholinergic beneficial effects, including Aß brain load reduction, neuroprotective and anti-inflammatory effects in the AD mouse models.

[Intranasal absorption of rivastigmine hydrogen tartrate and brain targeting evaluation].

To investigate factors influencing the intranasal absorption of rivastigmine hydrogen tartrate (RHT), we studied the pharmacokinetics of RHT after intranasal administration and evaluated its brain targeting behavior. In situ rat nasal perfusion model was used in the study and pH impact was examined on the intranasal absorption of RHT. High performance liquid chromatography (HPLC) method was established to measure RHT concentration in the plasma and brain tissue after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting index(DTI), and nose-to-brain direct transport percentage (DTP) were calculated. It was demonstrated that the intranasal absorption mechanism of RHT was passive diffusion. The absorption rate was highest at pH 6.0. The absolute bioavailability of intranasally administrated RHT was 73.58%. Compared with that of intravenous administration, RHT absorption into the brain was faster and more efficient after intranasal delivery, and the DTI value was 195.27% of intravenous injection. Moreover, 48.79% of the drug can be absorbed directly from the nose into the brain without systematic circulation. Meanwhile, drug elimination half-time in the brain was prolonged by 1.4 fold compared to that of intravenous injection. In conclusion, intranasal administration of RHT not only improves drug absorption into the system, but also enhances drug absorption rate and content in the brain remarkably, which is an advantage in the treatment of central nervous system-related diseases.

Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data.

Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.