Maximum Drug Concentration Research Articles

Improved functional biomechanics during squat following an exercise program targeting excessive anterior pelvic tilt in patients with symptomatic hip dysplasia

The goal of this study was to identify cocktails of drugs able to protect cultured rodent cortical neurons against increasing durations of oxygen-glucose deprivation (OGD). As expected, a cocktail composed of an NMDA and AMPA receptor antagonists and a voltage gated Ca2+ channel blocker (MK-801, CNQX and nifedipine, respectively) provided complete neuroprotection against mild OGD. Increasingly longer durations of OGD necessitated increasing the doses of MK-801 and CNQX, until these cocktails ultimately failed to provide neuroprotection against supra-lethal OGD, even at maximal drug concentrations. Surprisingly, supplementation of any of these cocktails with blockers of TRPM7 channels for increasing OGD durations was not neuroprotective, unless these blockers possessed the ability to inhibit NMDA receptors. Supplementation of the maximally effective cocktail with other NMDA receptor antagonists augmented neuroprotection, suggesting insufficient NMDAR blockade by MK-801. Substitution of MK-801 in cocktails with high concentrations of a glycine site NMDA receptor antagonist caused the greatest improvements in neuroprotection, with the more potent SM-31900 superior to L689,560. Substitution of CQNX in cocktails with AMPA receptor antagonists at high concentrations also improved neuroprotection, particularly with the combination of SYM2206 and NBQX. The most neuroprotective cocktail was thus composed of SM-31900, SYM2206, NBQX, nifedipine and the antioxidant trolox. Thus, the cumulative properties of antagonist potency and concentration in a cocktail dictate neuroprotective efficacy. The central target of supra-lethal OGD is excitotoxicity, which must be blocked to the greatest extent possible to minimize ion influx.

Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach.

Background: Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail.Methods: Healthy young participants (n = 20), healthy elderly participants (n = 16) and elderly patients with CKD (n = 17) received, in study period 1, a single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After a 14-day wash-out period, healthy young participants continued to study period 2 with the microdose cocktail plus rifampicin. PK parameters including area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (Cmax), and half-life were estimated before making pairwise comparisons of geometric mean ratios (GMR) between groups.Results: AUC and Cmax GMR (95% confidence interval; CI) of midazolam, a CYP3A probe substrate, were increased 2.30 (1.70–3.09) and 2.90 (2.16–3.88) fold in healthy elderly and elderly patients with CKD, respectively, together with a prolonged half-life. AUC and Cmax GMR (95%CI) of atorvastatin, another CYP3A substrate, was increased 2.14 (1.52–3.02) fold in healthy elderly and 4.15 (2.98–5.79) fold in elderly patients with CKD, indicating decreased CYP3A activity related to ageing. Associated AUC changes in the probe drug whose activity could be modified by intestinal P-glycoprotein (P-gp) activity, dabigatran etexilate, were observed in patients with CKD. However, whether the activity of pitavastatin and rosuvastatin is modified by organic anion transporting polypeptide 1B (OATP1B) and of breast cancer resistance protein (BCRP), respectively, in elderly participants with or without CKD was inconclusive.Conclusions: CYP3A activity is reduced in ageing. Intestinal P-gp function might be affected by CKD, but further confirmation appears warranted.Clinical Trial Registration:http://www.thaiclinicaltrials.org/ (TCTR 20180312002 registered on March 07, 2018)

A Method to Custom-build Equations of Drug Concentration as a Function of Real Time in the One-Compartment Open Model and Their Application in Multiple Intravenous Bolus and Multiple Oral Doses

A method to custom-build expressions of drug concentration as a function of total time in a one-compartment pharmacokinetic model for multiple-dose schedules is developed and successfully applied in four dosing schedules that combined administration of multiple IV bolus and oral maintenance and loading doses. The method consists of writing the terms of the mathematical sequence from the analytical solutions to drug concentration using total time, instead of time within dosing interval, extracting the pattern of the respective sequences, and finally, determining the partial sums of the series that relate to drug concentration to dose number and real-time, for each particular administration route and dosing schedule. Multiple subroutines written in Fortran language demonstrated the potential of these equations to investigate the effect of dose size on peak plasma drug concentration and peak time after multiple oral administrations and for calculating and refining experimentally determined time-dependent pharmacokinetic parameters such as non steady-state average concentration values and Area Under the Curve (AUC). It is shown that the only truly independent of dose size peak time is that of the first oral dose (). A mathematical expression was derived that relates the time to reach non steady-state peak times after multiple oral doses to the absorption and elimination rate constants for the first time. For repetitive oral dose administration, the will always be the longest peak time, while the shortest time to reach maximum plasma drug concentration will be at steady-state conditions.

Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.

Influence of FMO3 and CYP3A4 Polymorphisms on the Pharmacokinetics of Teneligliptin in Humans.

Teneligliptin, a dipeptidyl peptidase-4 inhibitor, is used to treat type 2 diabetes mellitus. FMO3 and CYP3A4 metabolize teneligliptin into teneligliptin sulfoxide. This study examined the effects of FMO3 (rs909530, rs1800822, rs2266780, and rs2266782) and CYP3A4 (rs2242480) polymorphisms on teneligliptin pharmacokinetics at a steady state among 23 healthy participants administered 20 mg teneligliptin daily for 6 days. Subjects with FMO3 rs909530, rs2266780, and rs2266782 polymorphisms exhibited a significant gene dosage-dependent increase in maximum steady-state plasma drug concentration (Cmax,ss) and area under the drug concentration vs time curve (AUC) (p<0.05). However, the Cmax values significantly decreased but the AUC values did not significantly vary in subjects with CYP3A4 polymorphism (rs2242480). These results suggest that FMO3 and CYP3A4 polymorphisms affect teneligliptin pharmacokinetics in humans. The findings of this study provide a scientific basis for the inter-individual variation in teneligliptin disposition.

PREPARATION AND IN VIVO EVALUATION OF CANDESARTAN CILEXETIL SOLID DISPERSIONS

Objective: The present study aims at development of solid dispersions (SD) of candesartan cilexetil for enhanced solubility and bioavailability. Methods: About 18 SD formulations of candesartan cilexetil were prepared by solvent evaporation technique and evaluated. The in vitro release studies were conducted and the best formulation chosen was further characterized for Fourier transform infrared spectroscopy, Scanning electron microscope, X-ray, and stability. The in vivo evaluation study conducted in rats. Results: The formulation SD16 containing drug and Soluplus in 1:3 ratio along with 2% selective laser sintering was chosen optimal based on drug content (99.08%), and drug release (99.7%). In vivo studies conducted on SD16 showed that mean time to peak concentration (Tmax) was 2.0±0.05 and 4±0.2 h for the optimized and pure drug, respectively, while mean maximum drug concentration (Cmax) was 570.63±2.65 ng/mL and was significant as compared to the candesartan pure drug 175.146±0.07 ng/mL. Area under curve AUC0-∞ infinity for candesartan SD16 was higher (4860.61±1.05 ng.h/ml) than pure drug suspension 1480±1.72 ng.h/ml. Conclusion: Hence, the developed SD formulations enhanced the bioavailability of drug by 3 folds.

Twenty-four-week interim outcomes of bedaquiline-containing regimens in treatment of adolescents with rifampicin-resistant tuberculosis: A retrospective cohort study in China.

To evaluate the 24-week interim outcomes of bedaquiline-containing regimens in the treatment of adolescents with rifampicin-resistant tuberculosis (RR-TB) in China. Adolescents with RR-TB from two hospitals were included in this retrospective study. All patients received the longer regimen containing bedaquiline. Sputum culture, chest computed tomography, blood tests and electrocardiography were performed regularly, and the outcomes after 24 weeks of treatment were reported. Four male and six female adolescents aged 11 to 17 years old were included. Among them, four (40.0%), four (40.0%) and two (20.0%) were confirmed to have RR-TB, multidrug-resistant TB and extensively drug-resistant TB, respectively. The most common companion drugs included linezolid (100.0%), cycloserine (90.0%), pyrazinamide (80.0%), moxifloxacin (50.0%) and levofloxacin (40.0%). Culture conversion rates of 80.0%, 100.0% and 100.0% were observed at weeks 2, 4 and 24, respectively. The mean maximum drug concentration of bedaquiline at weeks 2, 12 and 24 was 3.29 ± 0.66, 1.78 ± 0.81 and 1.93 ± 0.74 μg/mL, respectively. Six adverse events including leukopenia (50.0%), Fridericia-corrected QT (QTcF) interval prolongation (16.7%), anaemia (16.7%) and peripheral neuropathy (16.7%) were observed in five (50.0%) patients. No patient discontinued bedaquiline owing to QTcF interval prolongation. Meanwhile, no deaths, reversions or serious adverse events were reported during 24 weeks of treatment. A longer regimen containing bedaquiline was effective and well tolerated in Chinese adolescents with RR-TB. The combination of bedaquiline and linezolid may be a favourable choice for this population.

In Vitro, In Vivo, and Absorption, Distribution, Metabolism, and Excretion Evaluation of SF5-Containing N,N'-Diarylureas as Antischistosomal Agents.

In recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group (SF5). Low 50% inhibitory concentration (IC50) values for Schistosoma mansoni newly transformed schistosomula (0.6 to 7.7 μM) and adult worms (0.1 to 1.6 μM) were observed. Four selected compounds that were highly active in the presence of albumin (>70% at 10 μM), endowed with decent cytotoxicity profiles (selectivity index [SI] against L6 cells >8.5), and good microsomal hepatic stability (>62.5% of drug remaining after 60 min) were tested in S. mansoni-infected mice. Despite the promising in vitro worm-killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.

Evaluation of drug-drug interactions of pemigatinib in healthy participants.

Pemigatinib (INCB054828), a potent and selective oral fibroblast growth factor receptor 1-3 inhibitor, is a Biopharmaceutical Classification System class II compound with good permeability and pH-dependent solubility that is predominantly metabolized by cytochrome P450 (CYP) 3A. Two drug-drug interaction studies, one with acid-reducing agents, esomeprazole (proton pump inhibitor [PPI]) and ranitidine (histamine-2 [H2] antagonist), and the other with potent CYP3A-modulating agents, itraconazole (CYP3A inhibitor) and rifampin (CYP3A inducer), were performed. Both were open-label, fixed-sequence studies conducted in up to 36 healthy participants each, enrolled into two cohorts (n = 18 each). Pemigatinib plasma concentration was measured, and pharmacokinetic parameters were derived by non-compartmental analysis. There was an 88% and 17% increase in pemigatinib area under the plasma drug concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), respectively, with itraconazole, and an 85% and 62% decrease in pemigatinib AUC and Cmax with rifampin coadministration. There was a 35% and 8% decrease in pemigatinib AUC and Cmax, respectively, with esomeprazole, and a 2% decrease in Cmax and 3% increase in AUC with ranitidine coadministration. In both studies, all adverse events reported were grade ≤ 2. Coadministration with itraconazole or rifampin resulted in a clinically significant change in pemigatinib exposure. Therefore, coadministration of strong CYP3A inducers with pemigatinib should be avoided, and the dose of pemigatinib should be reduced if coadministration with strong CYP3A inhibitors cannot be avoided. The effect of PPIs/H2 antagonists on pemigatinib exposure was modest, and pemigatinib can be administered without regard to coadministration of PPIs/H2 antagonists.

Nose-to-brain delivery of phenytoin and its hydrophilic prodrug fosphenytoin combined in a microemulsion - formulation development and in vivo pharmacokinetics.

Phenytoin is a low aqueous solubility antiepileptic drug, but its phosphate ester prodrug fosphenytoin is soluble, although less permeable. In a previous study, the intranasal administration of aqueous-based formulations of fosphenytoin led to high but delayed phenytoin bioavailability compared to the intravenous route. In this work, we hypothesized that formulating an association of the prodrug fosphenytoin and the drug phenytoin (the active and diffusible form), could result in a faster and/or more effective brain targeting. Hence, nano or microemulsions containing both active drug and prodrug were developed and characterized regarding viscosity, osmolality, pH, mean size and in vitro drug release. Then, in vivo pharmacokinetics of a selected microemulsion containing fosphenytoin and phenytoin was evaluated in mice following intranasal administration and compared with a similar microemulsion containing fosphenytoin only. Both microemulsions led to higher brain drug levels at short time points than previously developed simpler aqueous based fosphenytoin formulations, likely due to the microemulsion's permeation enhancing effect. In addition, having a small amount of phenytoin in the formulation led to an equivalent maximum brain drug concentration and an overall higher absolute bioavailability, with a prolonged drug exposure. Hence, it can be concluded that if there is a need for a fast and prolonged therapeutic effect, a drug/phosphate ester prodrug combination in a microemulsion is ideal, but if a fast effect is all that is needed, having the prodrug alone could be enough, while considering a formulation with permeation enhancing components.

Pharmacokinetic Modeling of Morphine's Effect on Plasma Concentrations of Ticagrelor and Its Metabolite in Healthy Volunteers.

This study aimed to build a mathematical model describing the pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) in a stable setting with concomitant administration of morphine. The model consists of a set of four differential equations prepared upon the available knowledge regarding the biological processes in the pharmacokinetics of ticagrelor. The set of equations was solved numerically using the Runge–Kutta method. The data were obtained in a double-blind, randomized, placebo-controlled, crossover trial. Twenty-four healthy volunteers received a 180-mg ticagrelor loading dose together with either 5-mg morphine or placebo. Blood samples were analyzed with liquid chromatography–tandem mass spectrometry to assess plasma concentrations of ticagrelor and AR-C124910XX before ticagrelor loading dose and after that 1, 2, 3, 4, and 6 h. The model allowed us to reproduce the experimental results accurately and led us to conclusions consistent with clinical observations that morphine delays the time of maximum drug concentration and that the morphine effect occurs due to decreased gastrointestinal motility. Based on the model, we were able to predict the effect of drug dose on receptor blocking efficacy.

Biomaterial implants in the treatment of oncology: a review

In globally, cancer is a second leading disease next to cardiovascular diseases in non-communicable diseases, which affect the all ages, sex, social status, ethnicity and primary cause of illness related death. Traditionally, systemic delivery drug systems like chemotherapy via oral capsule, injections of nanoparticles/micro particles, immunotherapy and others, which can inhibit or halt the progression of tumors. The short half-life of drugs which cannot achieve the targeted dose level to the tumor site and not able to target desired cell and commonly produces the organ toxicity. Recently, researchers have been attempting to direct delivery agents for cancer therapy. One of the best methods is a local therapy system, which deliver the drug directly via implantable procedure and it’s achieved the maximum concentration of the desire drug at the tumor site, non-target systemic exposure and minimize the organ toxicity to the patients. Biomaterial implants are widely used in the local concurrent delivery of chemotherapy and anti-angiogenic agents, local delivery of poly-chemotherapy, gene therapy as an alternative to drug delivery, scaffolds for cancer immunotherapy and polymer-based composites of drug molecules. There are different types of polymers like poly anhydride poly [bis (p-carboxy-phenoxy) propane-sebacic acid] copolymer [p(CPP:SA)], fatty acid dimer-sebacic acid copolymer (FAD-SA), poly (lactic-co-glycolic acid) copolymer (PLGA), poly (ε-caprolactone) (PCL), poly (glycerol monostearate-co-caprolactone), alginate and silica, used in successively cancer therapy. In order to minimize the risk of unwanted side effect of different types of biomaterials implants, it’s biocompatible to reduce the ability to elicit the inflammatory effect to the implanted area or the site. Therefore, the key role of choosing the appropriate and biocompatible implants to particular therapy is an indispensable. This should be validated with respect to risk benefit ratio in case of cancers. Biomaterial based implant local delivery systems provide more versatile and tailorable approach to against treatment of different types of the cancer.

Improvements in Glycemic Control Achieved by Altering the tmax Setting in the iLet® Bionic Pancreas When Using Fast-Acting Insulin Aspart: A Randomized Trial.

IntroductionWe investigated the safety of, and glucose control by, the insulin-only configuration of the iLet® bionic pancreas delivering fast-acting insulin aspart (faster aspart), using the same insulin-dosing algorithm but different time to maximal serum drug concentration (tmax) settings, in adults with type 1 diabetes.MethodsWe performed a single-center, single-blinded, crossover (two 7-day treatment periods) escalation trial over three sequential cohorts. Participants from each cohort were randomized to a default tmax setting (t65 [tmax = 65 min]) followed by a non-default tmax setting (t50 [tmax = 50 min; cohort 1], t40 [tmax = 40 min; cohort 2], t30 [tmax = 30 min; cohort 3]), or vice versa, all with faster aspart. Each cohort randomized eight new participants if escalation-stopping criteria were not met in the previous cohort.ResultsOverall, 24 participants were randomized into three cohorts. Two participants discontinued treatment, one due to reported ‘low blood glucose’ during the first treatment period of cohort 3 (t30). Mean time in low sensor glucose (< 54 mg/dl, primary endpoint) was < 1.0% for all tmax settings. Mean sensor glucose in cohorts 1 and 2 was significantly lower at non-default versus default tmax settings, with comparable insulin dosing. The mean time sensor glucose was in range (70–180 mg/dl) was > 70% for all cohorts, except the default tmax setting in cohort 1. No severe hypoglycemic episodes were reported. Furthermore, there were no clinically significant differences in adverse events between the groups.ConclusionThere were no safety concerns with faster aspart in the iLet at non-default tmax settings. Improvements were observed in mean sensor glucose without increases in low sensor glucose at non-default tmax settings.Trial RegistrationClinicalTrials.gov, NCT03816761.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01087-x.

A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers

PurposeTo compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males.MethodsIn this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration–time profile (AUC) from time zero extrapolated to infinity (AUC0–inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study.ResultsPharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0–inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0–inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80–125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study.ConclusionHLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963).Clinical trial registrationThe study was registered with Clinicaltrials.gov, NCT03483649.

IN VIVO EVALUATION OF QUINAPRIL TRILAYERED MATRIX TABLETS

Objective: The aim was to design, formulate, and evaluate the trilayer matrix tablets incorporated with quinapril for extend drug release.&#x0D; Methods: Quinapril trilayer matrix tablets were formulated using design of experiment software wherein initially 27 formulations (QF1-QF27) were designed for active layer from which one best formulation was chosen based on drug content, swelling index and in vitro release studies. The chosen formulation was formulated into extended release trilayed matrix tablet by varying proportions of polymers by direct compression and was evaluated for various physicochemical parameters, drug release. Best formulation was characterized for Fourier transform infrared (FTIR), stability, and pharmacokinetic study.&#x0D; Results: Out of 27 formulations highest drug release was exhibited by QF16 (98.85%) which was formulated into trilayer matrix tablets (AQF16- HQF16). Out of which EQF16 was found to exhibit highest values with 98.42% swelling index, 99.56% drug content, and 99.72% drug release in 24 h. All quinapril trilayer formulations showed zero-order and first-order for marketed product. The optimized formulation EQF16 was found to exhibit no interaction with excipients interpreted by FTIR and no significant changes were observed after loading for stability. In vivo studies conducted using optimized formulation EQF16 attained peak drug concentration (Tmax) of 4.0±0.06 and 1.0±0.03 h for the optimized and commercial formulations, respectively, while mean maximum drug concentration (Cmax) was 302.64±0.07 ng/mL and was significant (p&lt;0.05) as compared to the quinapril marketed product formulation 358.78±0.75 ng/mL.&#x0D; Conclusion: Hence, quinapril was successfully formulated into trilayer matrix tablet and found to be stable.

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 (n = 31) received irbesartan 1.5% and group 2 (n = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (Cmax), time of maximal drug concentration (Tmax), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the Cmax of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a Cmax of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while Cmax was below 2 ng/g for candesartan. For multiple dosing, the observed Cmean in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (Cmax 5.64 ± 4.08 ng/mL) and candesartan (Cmax 4.32 ± 1.04 ng/mL) were reached 0.5 h (Tmax) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit’s eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.

Optical Coherence Tomography and Microdialysis for Microneedle-Mediated Penetration Enhancement Study of Paeoniflorin-Loaded Ethosomes

Background: To understand the cumulative effect of topical formulations after medication, evaluate the therapeutic effect of microneedle-assisted (MN-assisted) paeoniflorin-loaded ethosomes (TGP-E), and explore the potential for deep penetration of drugs, this paper uses microdialysis to systematically study the percutaneous pharmacokinetics of TGP-E. Methods: First, optical coherence tomography (OCT) was used to study the effectiveness of microneedle puncture. Second, a microdialysis method and a UPLC-MS method for determining the amount of paeoniflorin (Pae) in dialysate were established. Finally, the transdermal pharmacokinetics of TGP-E was studied using in vivo microdialysis in rats under the above MN-assisted conditions. Results: The optimal MN-assisted conditions were obtained at a microneedle length of 500 μm, a pressure of 3 N, and an action time of 3 min. The pharmacokinetic results demonstrated that the maximum drug concentration (C_max) and the area under the curve (AUC) of the TGP-E gel were higher than the TGP-saline solution gel, and the mean retention time was lower. These indicated that microneedle can promote the entry of the ethosomes into the skin for in vivo experiments and greatly improve the possibility of deep penetration of the water-soluble Pae. Conclusion: Therefore, the microneedle-ethosomes delivery system is a more ideal means for promoting the deep penetration of Pae. These findings may provide a reference for the combination of multiple penetration-enhancement ways to promote drug absorption, and also provide a new insight to realize the development of novel, safe, and more effective dosage forms and administration routes of drugs.

Pharmacokinetic studies of ginsenosides Rk1 and Rg5 in rats by UFLC–MS/MS

A rapid ultra-fast liquid chromatography tandem mass spectrometry method was developed and validated to determine ginsenosides Rk1 and Rg5, a pair of isomers, in rat plasma, which was successfully applied to their pharmacokinetic studies. Two ginsenosides were given to male Sprague-Dawley rats via intragastrical and intravenous routes, respectively, and the impact of double bond position on the pharmacokinetic features of the two ginsenosides was elucidated in rats. Ginsenoside Rg3 was used as internal standard and ethyl acetate was applied to extract analytes and internal standard. Chromatographic separation was carried out on a reverse-phase UPLC HSS T3 column (100 × 2.1 mm, 1.8 μm). The flow rate was set to 0.4 ml/min. The fragmentation transition was m/z 765.4 → m/z 101.1 for two ginsenosides. The mobile phases were composed of 0.1% formic acid aqueous solution and acetonitrile. The linear range was 2-1,000 ng/ml for the two ginsenosides. Intra- and inter-day precisions were <11.67%, and accuracy fluctuated from -7.44 to 6.78%. The extraction recovery, matrix effect and stability were within acceptable levels. After treatment with ginsenosides Rk1 and Rg5, some differences were found in their pharmacokinetic profiles in rats. The maximum plasma drug concentration and the area under the plasma drug concentration-time curve of ginsenoside Rg5 were about 5 times bigger than those of ginsenoside Rk1 after oral administration, and 3 times higher after intravenous administration. The oral bioavailabilities of ginsenosides Rk1 and Rg5 were 0.67 and 0.97%, respectively. The results indicated that ∆20(22) -ginsenosides showed better pharmacokinetic features than ∆20(21) -ginsenosides with the same glycosylation.

Shared IVIVR for Five Commercial Enabling Formulations Using the BiPHa+ Biphasic Dissolution Assay.

The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. The in vitro partitioning profiles in the organic phase were compared with human pharmacokinetic data obtained from literature. In the first part, a meaningful in vitro dose of the formulations was assessed by determining the maximum drug concentration in the artificial absorption sink during dissolution (organic 1-decanol layer, Cdec,max). Then, the maximum concentration of the partitioned drug in the organic layer was correlated with the in vivo fraction absorbed, which was derived from published human pharmacokinetic data. Fraction absorbed represents the percentage, which is absorbed from the intestine without considering first pass. It was found that the maximum drug concentration in the organic phase obtained from an in vitro dose of ten milligrams, which is equivalent to 15–25 µmol of the respective drug, led to the highest congruency with the fraction absorbed in vivo. In the second part, the in vivo relevance of the BiPHa+ dissolution data was verified by establishing a shared in vitro/in vivo relationship including all formulations. Based on the in vitro kinetics of the BiPHa+ experiments human in vivo plasma profiles were predicted using convolutional modelling approach. Subsequently, the calculated pharmacokinetic profiles were compared with in vivo performance of the studied drug products to assess the predictive power of the BiPHa+ assay. The BiPHa+ assay demonstrated biorelevance for the investigated in vitro partitioning profiles using a single set of assay parameters, which was verified based on human pharmacokinetic data of the five drug products.

Antipsychotic Potential and Safety Profile of TPGS-Based Mucoadhesive Aripiprazole Nanoemulsion: Development and Optimization for Nose-To-Brain Delivery.

Delivering therapeutics to the brain using conventional dosage forms is always a challenge, thus the present study was aimed to formulate mucoadhesive nanoemulsion (MNE) of aripiprazole (ARP) for intranasal delivery to transport the drug directly to the brain. Therefore, a TPGS based ARP-MNE was formulated and optimized using the Box-Behnken statistical design. The improved invitro release profile of the formulation was in agreement to enhanced exvivo permeation through sheep mucous membranes with a maximum rate of permeation co-efficient (62.87cmh-1×103) and flux (31.43μgcm-2.h-1). The pharmacokinetic profile following single-dose administration showed the maximum concentration of drug in the brain (Cmax) of 15.19±2.51μgmL-1 and Tmax of 1h in animals with ARP-MNE as compared to 10.57±1.88μgmL-1 and 1h, and 2.52±0.38μgmL-1 and 3h upon intranasal and intravenous administration of ARP-NE, respectively. Further, higher values of % drug targeting efficiency (96.9%) and % drug targeting potential (89.73%) of ARP-MNE through intranasal administration were investigated. The studies in Wistar rats showed no existence of extrapyramidal symptoms through the catalepsy test and forelimb retraction results. No exvivo ciliotoxicity on nasal mucosa reflects the safety of the components and delivery tool. Further, findings on locomotor activity and hind-limb retraction test in ARP-MNE treated animals established its antipsychotic efficacy. Thus, it can be inferred that the developed ARP-MNE could effectively be explored as brain delivery cargo in the effective treatment of schizophrenia without producing any toxic manifestation.