Akiko Kiriyama

Availability of polymeric nanoparticles for specific enhanced and targeted drug delivery

Over the past 20-30 years there has been quite a number of studies interested in polymeric nanoparticle (PNP) systems as a pharmaceutical approach for poorly soluble drugs, peptide drugs, gene and antibodies. Now, the products based on the PNP technologies are used in the fields of medical science, pharmaceutical science, tissue engineering and clothing, food and housing. This review focuses attention on PNPs for specific enhanced and targeted drug delivery of therapeutic drugs including peptide drugs as well as drug delivery applications of such systems. Outcomes from recent studies on polymers, how to make PNPs, pharmacokinetics and pharmacodynamics of PNPs, and the release profiles from PNPs and related systems are also described, including their pharmacokinetics and pharmacodynamics, if available. In addition, the latest PNP trends and will be described.

Binding of multivalent anionic porphyrins to V3 loop fragments of an HIV-1 envelope and their antiviral activity.

Interactions of multivalent anionic porphyrins and their iron(III) complexes with cationic peptides, V3(Ba-L) and V3(IIIB), which correspond to those of the V3 loop regions of the gp120 envelope proteins of the HIV-1(Ba-L) and HIV-1(IIIB) strains, respectively, are studied by UV/Vis, circular dichroism, (1)H NMR, and EPR spectroscopy, a microcalorimetric titration method, and anti-HIV assays. Tetrakis(3,5-dicarboxylatophenyl)porphyrin (P1), tetrakis[4-(3,5-dicarboxylatophenylmethoxy)phenyl]porphyrin (P2), and their ferric complexes (Fe(III)P1 and Fe(III)P2) were used as the multivalent anionic porphyrins. P1 and Fe(III)P1 formed stable complexes with both V3 peptides (binding constant K>10(6) M(-1)) through combined electrostatic and van der Waals interactions. Coordination of the His residues in V3(Ba-L) to the iron center of Fe(III)P1 also played an important role in the complex stabilization. As P2 and Fe(III)P2 form self-aggregates in aqueous solution even at low concentrations, detailed analysis of their interactions with the V3 peptides could not be performed. To ascertain whether the results obtained in the model system are applicable to a real biological system, anti-HIV-1(BA-L) and HIV-1(IIIB) activity of the porphyrins is examined by multiple nuclear activation of a galactosidase indicator (MAGI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. There is little correlation between chemical analysis and actual anti-HIV activity, and the size rather than the number of the anionic groups of the porphyrin is important for anti-HIV activity. All the porphyrins show high selectivity, low cytotoxicity, and high viral activity. Fe(III)P1 and Fe(III)P2 are used for the pharmacokinetic study. Half-lives of these iron porphyrins in serum of male Wistar rats are around 4 to 6 h owing to strong interaction of these porphyrins with serum albumin.

Delivery of Oxytocin to the Brain for the Treatment of Autism Spectrum Disorder by Nasal Application

Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the bloodstream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application. The aim of this study is to evaluate the disposition, nasal absorption, and therapeutic potential of OXT after nasal administration. The pharmacokinetics of OXT after intravenous bolus injection to rats followed a two-compartment model, with a rapid initial half-life of 3 min. The nasal bioavailability of OXT was approximately 2%. The brain concentration of OXT after nasal application was much higher than that after intravenous application, despite much lower concentrations in the plasma. More than 95% of OXT in the brain was directly transported from the nasal cavity. The in vivo stress-relief effect by OXT was observed only after intranasal administration. These results indicate that pharmacologically active OXT was effectively delivered to the brain after intranasal administration. In conclusion, the nasal cavity is a promising route for the efficient delivery of OXT to the brain.

Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting

In this study, we developed nano-fiber-based tablets with acetaminophen (AAP; LogPow=0.51) for controlled-release delivery systems and evaluated in vitro drug dissolution and in vivo pharmacokinetics in rats. Nano-fibers made from methacrylic acid copolymer S (MAC; EUDRAGIT S100) and containing AAP were prepared using a solvent-based electrospinning (ES) method. In vitro dissolution rate profiles of AAP showed tableting pressure-dependent decreases and pH-dependent increases. The results of tablet tracking by X-ray irradiation showed tablets based on MAC nano-fibers did not disintegrate in the upper intestinal lumen and had the properties of a long-term-acting tablet. In addition, the in vitro release profiles of AAP from nano-fiber tablets prepared by dissolving MAC with AAP (NFT), nano-fiber tablets prepared by adsorbing AAP to drug-free MAC nano-fibers (NFTadso), and tablets prepared by adsorbing half the amount of AAP to MAC nano-fibers containing the remaining amount of AAP (NFThalf) showed independent controlled-release aspects of AAP compared with physical mixture tablets (PMT). In vivo pharmacokinetic studies in rats after intraduodenal administration of 14 mg/rat AAP in NFT, NFTadso, and NFThalf demonstrated that all these tablets based on MAC nano-fibers showed sustained-release profiles compared with PMT, and showed ultra-sustained release properties for AAP. These new tablets based on MAC nano-fibers did not disintegrate in the intestine in the lower pH region, and the tablets could regulate the release of AAP in a pH-dependent manner. The ES method is a useful technique to prepare nano-fibers and showed promising results as an oral delivery system for sustained-release regulation.

Simulations of Cytochrome P450 3A4-Mediated Drug-Drug Interactions by Simple Two-Compartment Model-Assisted Static Method

In order to predict cytochrome P450 3A4 (CYP3A4)-mediated drug-drug interactions (DDIs), a simple 2-compartment model-assisted, overall inhibition activity (Ai,overall) method was derived based on 2 concepts. One concept was that the increase in blood victim level and fold increase in the area under the blood victim level curve produced by DDI are determined entirely by Ai,overall, the hepatic availability of the victim and fraction of urinary excreted unchanged victim, where Ai,overall is determined by the perpetrator-specific CYP isoform inhibition activities (Ai,CYPs, DDI predictor-1) and victim-specific fractional CYP isoform contributions (fm,CYPs, predictor-2). The other concept was that a DDI can be bridged to other DDIs, so that any possible DDI produced by a given victim or a given perpetrator can be predicted by using these predictors. The Ai,CYP3A4s of 12 common CYP3A4 inhibitors were able to be determined and shown to be useful for the prediction of CYP3A4-mediated DDIs wherein victims were metabolized by multiple CYP isoforms. Additionally, it was demonstrated that fm,CYP values with high confidence can be estimated by bridging DDIs produced by the same victim and different perpetrators. This bridging approach will accelerate prediction of DDIs produced by new chemical entities from the existing DDI database.

Quantitative Estimation of the Effect of Nasal Mucociliary Function on In Vivo Absorption of Norfloxacin after Intranasal Administration to Rats

Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.

Novel strategy for improving the bioavailability of curcumin based on a new membrane transport mechanism that directly involves solid particles

Graphical abstract Figure. No Caption available. Abstract Amorphization has been widely recognized as a useful solubilization technique for poorly water‐soluble drugs, such as curcumin. We have recently reported the novel finding that the membrane transport of curcumin was markedly enhanced when amorphous solid particles of curcumin came into direct contact with the lipid membrane surface, but this was not true for crystalline solid particles. The increase in the permeation of curcumin was found to be independent of the improvements in aqueous solubility brought about by amorphization. Thus, we have identified a novel membrane transport mechanism that directly involves solid particles. In addition, it might represent a novel strategy for improving the bioavailability of curcumin that does not focus on the aqueous solubility of the drug. In this study, the direct effects of the administration of amorphous nanoparticles of curcumin (ANC) on the in vivo intestinal absorption of curcumin were investigated. After the intraduodenal administration of a curcumin suspension, the area under the curve of the plasma concentration of curcumin increased in a manner that was dependent on the curcumin concentration of the suspension, while no significant absorption was observed from a saturated solution. This finding is consistent with the results from our in vitro transepithelial transport study. In the latter experiment, the bioavailability of curcumin was found to be 1–2%. The intrapulmonary insufflation of ANC powder resulted in a significant increase in the bioavailability of curcumin (it was two orders of magnitude higher than that seen after the application of a crystalline suspension). This was due to the ANC particles coming into contact with epithelial cells in a more efficient manner after the pulmonary application of the ANC powder than after the intestinal application of the ANC suspension. Therefore, the pulmonary insufflation of amorphous powder is a novel approach to improving the bioavailability of curcumin and might be a useful way of increasing the bioavailability of poorly water‐soluble drugs, such as curcumin.

The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption

&NA; Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (VFMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro VFMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, kmc, was determined from the disappearance profiles of FMS. kmc was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between kmc and VFMS (r2 = 0.9745, p < 0.001). These results indicate that in vivo kmc can be estimated from the in vitro parameter, VFMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC. Graphical abstract Figure. No caption available.

Pharmacokinetic-Pharmacodynamic Analyses of Anti-diabetes, Glimepiride: Comparison of the Streptozotocin-Induced Diabetic, GK and Wistar Rats

Efficacy and safety of a drug and its plasma concentration are closely correlated, and plasma concentrations are used as an index of the drug’s effects. Therefore, it is important to understand the relationship between the drug’s plasma concentration and its effects. Plasma glucose control of diabetics retards its progression and glimepiride is widely used for its treatment. In the present study, pharmacokinetic-pharmacodynamic analysis of glimepiride was performed in Wistar rats, with normal plasma glucose levels (Normal), and streptozotocin-induced type 1 diabetes rats (Type 1) and type 2 diabetes GK rats (Type 2). The PK-PD model was structured to investigate time-dependent plasma glucose changes in relation to the plasma concentration, and the PK and PD characteristics of glimepiride were investigated. PK analysis of glimepiride in the three groups showed no significant differences in total body Clearance (CL) and half-life of the β phase. Plasma concentration profiles at a 0.5 mg/kg dose increased in the following order; Type 1, Normal, and Type 2 groups. The area under the plasma concentration-time curves for glimepiride was dosedependent in Normal and Type 2 groups. The CL decreased in the Type 2 group compared to the other groups at a 0.5 mg/kg dose. The maximum decrease in the plasma glucose level was increased in the following order; Normal, Type 2, and Type 1. From the estimated PK-PD analysis, the plasma glimepiride concentration necessary to produce hypoglycemic effects was higher, and the responsiveness of the drug at a drug concentration at the half-maximum effect was quicker, in the Type 2 group compared to the other groups. These effects of glimepiride were considered to improve the pathological condition. This study of the PK-PD characteristics of glimepiride is useful for prediction of the influence of drug-drug interactions and the change in clinical conditions of patients.

Usefulness of Two-Compartment Model-Assisted and Static Overall Inhibitory-Activity Method for Prediction of Drug-Drug Interaction

Our study of drug-drug interaction (DDI) started with the clarification of unusually large DDI observed between ramelteon (RAM) and fluvoxamine (FLV). The main cause of this DDI was shown to be the extremely small hepatic availability of RAM (vFh). Traditional DDI prediction assuming the well-stirred hepatic extraction kinetic ignores the relative increase of vFh by DDI, while we could solve this problem by use of the tube model. Ultimately, we completed a simple and useful method for prediction of DDI. Currently, DDI prediction becomes more complex and difficult when examining issues such as dynamic changes in perpetrator level, inhibitory metabolites, etc. The regulatory agents recommend DDI prediction by use of some sophisticated methods. However, they seem problematic in requiring plural in vitro data that reduce the flexibility and accuracy of the simulation. In contrast, our method is based on the static and two-compartment models. The two-compartment model has advantages in that it uses common pharmacokinetics (PK) parameters determined from the actual clinical data, guaranteeing the simulation of the reference standard in DDI. Our studies confirmed that dynamic changes in perpetrator level do not make a difference between static and dynamic methods. DDIs perpetrated by FLV and itraconazole were successfully predicted by use of the present method where two DDI predictors [perpetrator-specific inhibitory activities toward CYP isoforms (pAi, CYPs) and victim-specific fractional CYP-isoform contributions to the clearance (vfm, CYPs)] are determined successively as shown in the graphical abstract. Accordingly, this approach will accelerate DDI prediction over the traditional methods.