The impact of the site of blood sampling on pharmacokinetic parameters following sublingual dosing to dogs

IntroductionDrugs are most commonly administered orally, but some potential drug candidates are not suited for oral administration due to poor absorption, high first pass metabolism or gastrointestinal side effects. The interest for transmucosal dosing for systemic drug delivery is increasing, e.g. buccal, sublingual and nasal routes. The evaluation of the systemic plasma concentration and the derivation of the pharmacokinetic parameters of candidate compounds in preclinical studies are essential for drug development. The effect of site of blood sampling on the measured drug concentration, in both animals and humans, is to some extent known but it is not always taken into consideration in the design of pharmacological and toxicological studies.MethodsBlood samples were collected both from leg and jugular veins from beagle dogs following a single sublingual dosing of Compound A in order to determine the impact of different sites of blood sampling on plasma pharmacokinetics. Plasma was prepared by centrifugation and plasma concentrations of Compound A were determined by protein precipitation and liquid chromatography followed by mass spectrometric detection. The pharmacokinetic parameters were calculated by non-compartment methods.ResultsSampling from the jugular vein resulted in higher and more variable exposure during the absorption phase compared to sampling from a leg vein. The plasma exposure in the jugular vein, in terms of C_max, was 4-fold compared to that in the leg vein and an approximately 2-fold bioavailability was observed.DiscussionThe aim of this investigation was to determine the impact of the different sites of blood sampling on assessing systemic plasma exposure and pharmacokinetic parameters for Compound A following sublingual dosing to dogs. The results demonstrate the significant impact that the site of blood sampling has on PK parameters, and raise concerns of using the jugular vein as a site of sampling after sublingual and other transmucosal routes of dosing in the head region.     

Hydroxocobalamin Uptake into the Cerebrospinal Fluid after Nasal and Intravenous Delivery in Rats and Humans

The possibility of direct transport of hydroxocobalamin from the nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in rats was investigated and the results were compared with a human study.

Hydroxocobalamin was given to rats (n=8) both intranasally (214 μg/rat) and intravenously (49.5 μg/rat) into the jugular vein using a Vascular Access Port (VAP). Prior to and after drug administration, blood and CSF samples were taken and analysed by radioimmunoassay.

The AUC_CSF/AUC_plasma ratio after nasal delivery does not differ from the ratio after intravenous infusion, indicating that hydroxocobalamin enters the CSF via the blood circulation across the blood–brain barrier (BBB). This same transport route is confirmed by the cumulative AUC-time profiles in CSF and plasma, demonstrating a 30 min delay between plasma absorption and CSF uptake of hydroxocobalamin in rats and in a comparative human study.

The present results in rats show that there is no additional uptake of hydroxocobalamin in the CSF after nasal delivery compared to intravenous administration, which is in accordance with the results found in humans. This indicates a predictive value of the used rat model for the human situation when studying the nose to CSF transport of drugs.     

The Design and Validation of a Novel Intravenous Microdialysis Probe: Application to Fluconazole Pharmacokinetics in the Freely-Moving Rat Model

Purpose. The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. Methods. An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. Results. There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T_1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p > 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. Conclusions. These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.     

Nasal Delivery of Insulin Using Novel Chitosan Based Formulations: A Comparative Study in Two Animal Models Between Simple Chitosan Formulations and Chitosan Nanoparticles

Purpose. To investigate whether the widely accepted advantages associated with the use of chitosan as a nasal drug delivery system, might be further improved by application of chitosan formulated as nanoparticles. Methods. Insulin-chitosan nanoparticles were prepared by the ionotropic gelation of chitosan glutamate and tripolyphosphate pentasodium and by simple complexation of insulin and chitosan. The nasal absorption of insulin after administration in chitosan nanoparticle formulations and in chitosan solution and powder formulations was evaluated in anaesthetised rats and/or in conscious sheep. Results. Insulin-chitosan nanoparticle formulations produced a pharmacological response in the two animal models, although in both cases the response in terms of lowering the blood glucose levels was less (to 52.9 or 59.7% of basal level in the rat, 72.6% in the sheep) than that of the nasal insulin chitosan solution formulation (40.1% in the rat, 53.0% in the sheep). The insulin-chitosan solution formulation was found to be significantly more effective than the complex and nanoparticle formulations. The hypoglycaemic response of the rat to the administration of post-loaded insulin-chitosan nanoparticles and insulin-loaded chitosan nanoparticles was comparable. As shown in the sheep model, the most effective chitosan formulation for nasal insulin absorption was a chitosan powder delivery system with a bioavailability of 17.0% as compared to 1.3% and 3.6% for the chitosan nanoparticles and chitosan solution formulations, respectively. Conclusion. It was shown conclusively that chitosan nanoparticles did not improve the absorption enhancing effect of chitosan in solution or powder form and that chitosan powder was the most effective formulation for nasal delivery of insulin in the sheep model.     

Influence of mode of intravenous administration and blood sample collection on rat pharmacokinetic data

The influence of the mode of intravenous dosing and blood sample collection on the pharmacokinetics of 4-[(3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2, 6-disilacyclohexane hydrochloride (I) was studied in the rat. Blood samples obtained from the tail and by exsanguination following injection of the 14C-labeled drug into the caudal vein, the jugular vein, and the heart were analyzed for total radioactivity, and the concentration profiles from the different treatments were compared. Dosing and sampling from the tail vein resulted in significantly different blood levels (and related pharmacokinetic parameters) when compared to other methods, probably attributable to a local depot effect. Intracardiac administration tended to cause higher drug levels in the heart than intravenous doses, although no significant differences were found between the respective blood concentrations. The results showed that caudal vein injection is a simple and adequate method of intravenous administration in rats designated for exsanguinated blood and tissue collection. For serial blood sampling in individual animals, the dose may be given via the jugular vein and the blood collected from the cut tail. These methods require little or no surgical preparations and are particularly suitable for prolonged sampling in studies where a relatively large number of animals are involved.     

Insulin Containing Nanocomplexes Formed by Self-Assembly from Biodegradable Amine-Modified Poly(Vinyl Alcohol)-Graft-Poly(<Emphasis Type="SmallCaps">l</Emphasis>-Lactide): Bioavailability and Nasal Tolerability in Rats

Purpose The bioavailability and local tolerability of insulin containing nanocomplexes from amine-modified poly(vinyl alcohol)-graft-poly(l-lactide) were studied in rats. Histology of the nasal epithelium was studied to document integrity of the mucosa. Methods Nanocomplexes (NC) were prepared by spontaneous self-assembly of insulin and the water-soluble amphiphilic polymer. Changes in blood glucose and insulin blood concentration were monitored in anesthetized rats using a glucose meter and enzyme-linked immunosorbent assay, respectively. Histological sections of the nasal cavity were examined after H&E staining by light microscopy. Results NC reduced blood glucose level in fasted healthy rats by 20% after 50–80 min and in streptozotocin induced diabetic rats by 30% within 75–95 min compared to basal levels. In both animal models significant concentrations of human insulin were detected, with relative bioavailabilities F_rel of 2.8 up to 8.3%. The more hydrophobic, lactic acid grafted polyester were more effective at a threefold higher polymer concentration, increasing the relative bioavailability F_rel of a 5 IU/kg dose from 2.8 to 5.7%. Histological examination of the nasal mucosa after 4 h showed no signs of toxicity at the site of nasal administration. Conclusions These results demonstrate that the NC significantly enhanced insulin absorption, suggesting that amphiphilic biodegradable comb-polymers offer a promising approach for nasal peptide delivery.     

Injection into the jugular vein among people who inject drugs in the United Kingdom: Prevalence,associated factors and harms

BackgroundWhile people who inject drugs (PWID) typically use peripheral veins, some inject into their central veins, including the femoral and jugular veins. Injection into the jugular vein can have serious adverse health consequences, including jugular vein thrombosis, deep neck infections, pneumothorax, endocarditis and sepsis. This study examined the prevalence of, and factors associated with, jugular vein injection among a large sample of PWID in the United Kingdom.MethodUnlinked anonymous surveys (2011–14) recruited PWID from agencies providing services to this population. Self-reported demographic and injection-related data were collected from consenting respondents using a brief questionnaire and dried blood spot samples were tested for exposure to HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV). Univariate and multivariable logistic regression were used to examine factors associated with jugular vein injection.ResultsAmong 5261 PWID, one third had injected into a central vein in the previous 28 days, including 6% (n = 339) who had injected into their jugular vein and 1% (n = 52) who had used this site exclusively for recent injections. Factors independently associated with recent jugular vein injection in multivariable analysis included female gender, a lifetime history of imprisonment, sharing needles and syringes, poly-drug injection and injection into multiple body sites. Jugular vein injection was also associated with experiencing injection-related injuries, although no associations were identified with respect to exposure to blood borne viral infections.ConclusionA significant minority of PWID inject into the jugular vein in the United Kingdom. Public health responses should investigate ways to support and promote good injection site management in order to minimise vascular damage and reduce problems with peripheral venous access. Women who inject drugs, PWID with a history of imprisonment and those people who are experiencing early signs of injection-related skin and soft tissue injuries are priority sub-populations for interventions.     

Biovector™ Nanoparticles Improve Antinociceptive Efficacy of Nasal Morphine

Purpose. We have studied the antinociceptive activity and blood andbrain delivery of nasal morphine with or without Biovectornanoparticles in mice. Methods. A tail flick assay was used to evaluate theantinociceptive activity. The kinetics of morphine were evaluated in blood andbrain, using tritiated morphine as tracer. Results. These nanoparticles were shown to increase the durationof the antinociceptive activity of morphine after nasal administration.This effect was not due to an increase of morphine in the blood; andthe analgesic activity of morphine in association with nanoparticleswas reversed by naloxone. The ED₅₀ value was 33.6 ±15.6 mg/kg for morphine alone and 14.4 ± 7.6 mg/kg in presenceof nanoparticles. They were only effective at low doses (1.5 to 2.5 g),a higher or a lower dose had no effect. No interaction was found betweennanoparticles and morphine. NaDOC, a permeation enhancer, was unable toimprove nasal morphine activity. Conclusions. These results show the presence of nanoparticles onlyat a very specific dose increases the antinociceptive activity of nasalmorphine in mice. The occurrence of a direct transport of morphinefrom the nasal mucosa to the brain is discussed.     

Local Absorption Kinetics of Levofloxacin from Intestinal Tract into Portal Vein in Conscious Rat Using Portal-Venous Concentration Difference

Purpose. The local absorption kinetics of levofloxacin from the intestinal tract was quantitatively evaluated by simultaneously measuring the portal and venous plasma concentrations in a conscious rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and pyloric veins, respectively. After oral or intravenous administration of levofloxacin, portal and venous concentrations of levofloxacin were simultaneously monitored. The absorption rate from the intestine into the portal system was calculated from the portal-venous difference in the plasma concentration of levofloxacin, considering the distribution of levofloxacin into erythrocytes. Portal blood flow rate was newly measured by an electromagnetic flow meter. Results. There was little portal-venous difference after an intravenous dose of levofloxacin. In contrast, after oral administration, the plasma concentration in the portal vein was constantly higher than that in the jugular vein, demonstrating that this difference was caused by the intestinal absorption of levofloxacin. Conclusions. Approximately 90% levofloxacin was absorbed as the intact form from the intestinal tract into the portal system. By considering the bioavailability of levofloxacin in rat, the hepatic extraction ratio in vivo of levofloxacin was estimated to be 30%. The mean local absorption time (t_a) was 1.44hr which coincided almost with the mean absorption time (MAT).     

Definition of pharmacokinetic parameters: Influence of the sampling site

Taking into account drug concentration differences within the circulatory system, a unique definition of each of the basic pharmacokinetic parameters, clearance (CL),steady-state volume of distribution (V _ss ),and mean disposition residence time (MDRT),is given which is generally valid for linear systems. The conventional relationship MDRT=V _ss /CLholds theoretically only in the case of right atrial sampling following bolus intravenous injection. The values based on blood drug concentration from a peripheral venous sampling site are influenced by the pharmacokinetic properties of the lungs and the sampling tissue. Practically, the pulmonary extraction ratio and the mean transit time through the sampling tissue may thereby be of particular importance. Thus the effect of the sampling site on the pharmacokinetic parameters estimated by standard (classical) methods is quantitatively explained.     

超声下两种颈内静脉置管法的比较

目的 超声下比较两种路径颈内静脉置管方法的准确性及并发症的发生率,寻找更安全、可靠的颈内静脉穿刺路径。方法 选择需行颈内静脉穿刺患者60例,随机分为传统中路法穿刺组(A组,n=30)与颈内静脉搏动点法穿刺组(B组,n=30)。观察颈总动脉直径(D1)、颈内静脉直径(D2)、颈总动脉和颈内静脉重叠覆盖率、穿刺路径距颈内静脉中心距离(D3)、穿刺路径距颈总动脉外侧距离(D4)及可能触及颈总动脉例数。结果 与A组比较,B组D3较小,差异有统计学意义(P<0.05);B组D4明显大于A组,差异有统计学意义(P<0.05)。结论 颈内静脉搏动点法行颈内静脉穿刺更准确,并发症发生率更低。     

Morphine Blood-Brain Barrier Transport Is Influenced by Probenecid Co-Administration

Purpose. The objective of this study was to investigate the possible influence of probenecid on morphine transport across the blood-brain barrier (BBB) in rats. Methods. Microdialysis probes, calibrated using retrodialysis by drug, were placed into the striatum and jugular vein of seven Sprague-Dawley rats. Morphine was administered as a 4-h exponential infusion. The experiment was repeated the next day with the addition of probenecid, administered as a bolus dose (20 mg/kg) followed by a constant infusion (20 mg/kg/h). Models for BBB transport were built using the computer program NONMEM. Results. The steady-state ratio of 0.29 ± 0.07 of unbound morphine concentration in brain to that in blood indicates that morphine is actively effluxed at the BBB. Probenecid co-administration increased the ratio to 0.39 ± 0.04 (p < 0.05). Models in which probenecid influenced the brain efflux clearance rather than the influx clearance, well described the data. The half-life in brain increased from 58 ± 9 min to 115 ± 25 min when probenecid was co-administered. Systemic clearance of morphine also decreased upon probenecid co-administration, and M3G formation was decreased. Conclusion. This study indicates that morphine is a substrate for the probenecid-sensitive transporters at the BBB. Co-administration of probenecid decreased the brain efflux clearance of morphine.     

Pharmacokinetic Model to Describe the Lymphatic Absorption of r-metHu-Leptin After Subcutaneous Injection to Sheep

Purpose. The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep. Methods. r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.15 mg/kg) into the interdigital space of the hind leg. The SC groups included a non-cannulated control group and a lymph-cannulated group, in which peripheral lymph was continuously collected from a cannula in the efferent popliteal lymph duct. Serum and lymph concentrations were determined by enzyme-linked immunosorbent assay and profiles were modeled using compartmental pharmacokinetic methods. The fraction of the dose reaching the systemic circulation (F _sys) and the proportions of the absorbed dose taken up via the blood (F _blood) and lymph (F _lymph) were determined. Results. Serum and lymph concentration vs. time profiles were well described by a two compartment model with parallel first order absorption into blood and lymph. F _sys for the SC control group was 60.4 ± 8.4%. In the lymph-cannulated group, 21.7 ± 6.4% of the dose was recovered in serum and 34.4 ± 9.7% was recovered in peripheral lymph giving a total fraction absorbed (F _abs) of 56.0 ± 10.3%. F _sys for the SC control group was not significantly different to F _abs in the lymph-cannulated group. Conclusion. This study has shown that the lymph represents the predominant pathway for absorption of r-metHu-Leptin after SC administration.     

美国FDA鼻用制剂相关个药指导原则汇总分析

目的 通过梳理美国食品药品监督管理局（Food and Drug Administration,FDA）发布的鼻用制剂相关个药指导原则,总结FDA对鼻用制剂仿制药的研究要求,为国内鼻用制剂仿制药开发和评价提供参考。方法 在FDA官网发布的个药指导原则中筛选出鼻用制剂相关指导原则,进行汇总分析。结果 目前FDA现行43个鼻用制剂相关个药指导原则,推荐的生物等效性方法包括体外生物等效性研究、药动学研究、比较临床终点研究方法等,因不同品种而有所区别。部分个药指导原则已收录先进的体外检测技术如形态定向拉曼光谱用于代替体内临床试验。本文对不同种类生物等效性试验的试验设计、主要研究终点和等效性标准方面进行了代表性描述。结论 本文对FDA发布的鼻用制剂相关个药指导原则进行了汇总分析,为国内鼻用制剂仿制药开发和评价提供参考。     

Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes

Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (<2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.     

Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac

Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (F_H) of diclofenac was estimated to be 63%.     

基于微透析技术的苦参碱凝胶经皮给药的药动学研究

目的 建立同步测定经皮给药制剂在皮肤、血液中药动学的方法,研究苦参碱凝胶在体内的药动学行为。方法 应用经体外和体内回收率校正建立的基于微透析探针的皮肤血液双位点同步微透析系统,通过在皮肤和颈静脉植入探针,在大鼠腹部脱毛部位给予苦参碱凝胶,连续收集探针中12 h的透析液,并采用LC-MS微量检测技术测定探针透析液中的药物浓度。结果 本研究成功构建了双位点同步微透析药动学评价系统,大鼠皮肤给予苦参碱凝胶后,皮肤中的药物浓度、AUC值、半衰期均显著高于血液中药物浓度。结论 本研究建立的微透析结合LC-MS的取样及检测技术为经皮给药制剂的药动学研究提供了新的技术平台。     

Insoluble Powder Formulation as an Effective Nasal Drug Delivery System

Purpose. To evaluate the utility of insoluble powder formulation for nasal systemic drug delivery. Methods. To compare the efficacy of liquid and powder formulations, the nasal absorption of drugs was examined in rats using hydrophilic compounds with various molecular weights (MW) such as phenol red, cyanocobalamin, and fluorescein isothiocyanate (FITC)-Dextrans, and several kinds of powder. Intranasal residence time was also compared among the different formulations. Results. All the drugs examined were absorbed through the nasal mucosa to varying extent; their systemic bioavailability decreased with increasing MW. Insoluble calcium carbonate (CaCO₃) powder formulation provided increased absorption of drugs over the wide range of MW from 354 to 77,000 Da. In the case of phenol red, intranasal administration as a CaCO₃ powder formulation resulted in a plasma concentration profile similar to that of an intravenous bolus dose due to its very rapid and complete absorption from the nasal cavity. Furthermore, improved bioavailability of FITC-Dextran (MW 4,400; FD-4) was also achieved with other insoluble powders as well as CaCO₃, but not with soluble powders such as lactose, d-sorbitol, and d-mannitol. Insoluble powder formulation prolonged the residence time of FD-4 within the nasal cavity. Conclusions. Insoluble powder formulations improve nasal bioavailability predominantly by retarding drug elimination from the absorption site and appear to be effective for nasal systemic drug delivery.     

Mutual Inhibition of the Insulin Absorption-Enhancing Properties of Dodecylmaltoside and Dimethyl-β-cyclodextrin Following Nasal Administration

Purpose. To determine if a nasal insulin formulation containing two distinct absorption–enhancing agents exhibits an additive or synergistic increase in the rate of systemic insulin absorption. Methods. The pharmacokinetics and pharmacodynamics of insulin absorption were measured in hyperglycemic anesthetized rats following nasal insulin administration with formulations containing two different types of absorption–promoting agents, dimethyl––cyclodextrin (DMBCD) and dodecylmaltoside (DDM). Results. When either DDM (0.1–0.5%) or DMBCD (1.0–5.0%) was added to the nasal insulin formulation, a significant and rapid increase in plasma insulin levels was observed, with a concomitant decrease in blood glucose concentration. A combined preparation containing 0.25% DDM (0.005 M) and 2.5% DMBCD (0.019M), however, failed to cause an increase in plasma insulin levels or a decrease in blood glucose concentration. Increasing concentrations of DDM added to an insulin formulation with a fixed DMBCD concentration caused a decrease, rather than an increase, in systemic absorption of insulin. Conclusions. Mixing DMBCD and DDM resulted in mutual inhibition of their ability to enhance systemic absorption of insulin following nasal delivery. The results are consistent with the formation of an inclusion complex between DDM and DMBCD which lacks the ability to enhance nasal insulin absorption.     

Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting

Abstract

The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood–brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.