Confocal Laser Scanning Microscopic Visualization of the Transport of Dextrans After Nasal Administration to Rats: Effects of Absorption Enhancers

Purpose. To visualize the transport pathway(s) of high molecular weight model compounds across rat nasal epithelium in vivousing confocal laser scanning microscopy. Furthermore, the influence of nasal absorption enhancers (randomly methylated -cyclodextrin and sodium taurodihydrofusidate) on this transport was studied. Methods. Fluorescein isothiocyanate (FITC)-labelled dextrans with a molecular weight of 3,000 or 10,000 Da were administered intranasally to rats. Fifteen minutes after administration the tissue was fixed with Bouin. The nasal septum was surgically removed and stained with Evans Blue protein stain or DiIC18(5) lipid stain prior to visualization with the confocal laser scanning microscope. Results. Transport of FITC-dextran 3,000 across nasal epithelium occurred via the paracellular pathway. Endocytosis of FITC-dextran 3,000 was also shown. In the presence of randomly methylated -cyclodextrin 2% (w/v) similar transport pathways for FITC-dextran 3,000 were observed. With sodium taurodihydrofusidate 1% (w/v) the transport route was also paracellular with endocytosis, but cells were swollen and mucus was extruded into the nasal cavity. For FITC-dextran 10,000 hardly any transport was observed without enhancer, or after co-administration with randomly methylated -cyclodextrin 2% (w/v). Co-administration with sodium taurodihydrofusidate 1% (w/v) resulted in paracellular transport of FITC-dextran 10,000, but morphological changes, i.e. swelling of cells and mucus extrusion, were observed. Conclusions. Confocal laser scanning microscopy is a suitable approach to visualize the transport pathways of high molecular weight hydrophilic compounds across nasal epithelium, and to study the effects of absorption enhancers on drug transport and cell morphology.     

Absorption Enhancing Effect of Cyclodextrins on Intranasally Administered Insulin in Rats

The absorption enhancing effect of -, -, and -cyclodextrin (CD), dimethyl--cyclodextrin (DMCD), and hydroxypropyl--cyclodextrin (HPCD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DMCD to the insulin solution resulted in a high bioavailability, 108.9 ± 36.4% (mean ± SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% -CD gave rise to an insulin bioavailability of 27.7 ± 11.5% (mean ± SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the -CD-containing solution as compared to the DMCD preparation. The other CDs, HPCD (5%), -CD (1.8%), and -CD (5%), did not have significant effects on nasal insulin absorption. DMCD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DMCD is a potent enhancer of nasal insulin absorption in rats.     

Solubility of ( ± )-Ibuprofen and S ( + )-Ibuprofen in the Presence of Cosolvents and Cyclodextrins

Aqueous solubility is an important parameter for the development of liquid formulations and in the determination of bioavailability of oral dosage forms. Ibuprofen (IB), a nonsteroidal anti-inflammatory drug, is a chiral molecule and is currently used clinically as a racemate (racIB). However, the S form of ibuprofen or S(+)-ibuprofen (SIB) is the biologically active isomer and is primarily responsible for the anti-inflammatory activity. Phase solubility studies were carried out to compare the saturation solubilities of racIB and SIB in the presence of common pharmaceutical solvents such as glycerol, sorbitol solution, propylene glycol (PG), and polyethylene glycol (PEG 300) over the range of 20% to 80% v/v in aqueous based systems. The solubilities of the two compounds were also compared in the presence of cyclodextrins such as beta cyclodextrin (CD), hydroxypropyl beta cyclodextrin (HPCD), and beta cyclodextrin sulfobutyl ether sodium salt (CDSB) over the range of 5% to 25% w/v. Solubility determinations were carried at 25°C and 37°C. Cosolvents exponentially increased the solubility of both SIB and racIB, especially in the presence of PG and PEG 300. Glycerol was not very effective in increasing the aqueous solubilities of both compounds, whereas sorbitol solution had a minimal effect on their solubility. PG and PEG 300 increased the solubility of SIB by 400-fold and 1500-fold, respectively, whereas the rise in solubility for racIB was 193-fold and 700-fold, respectively, at 25°C for the highest concentration of the cosolvents used (80% v/v). Of the two compounds studied, higher equilibrium solubilities were observed for SIB as compared with racIB. The derivatized cyclodextrins increased the aqueous solubility of racIB and SIB in a concentration-dependent manner giving A_L type of phase diagrams. The phase solubility diagrams indicated the formation of soluble inclusion complexes between the drugs and HPCD and CDSB, which was of 1:1 stoichiometry. The addition of underivatized CD reduced the solubility of racIB and SIB via the formation of an insoluble complex. The S form formed more stable complexes with HPCD and CDSB as compared with racIB. The solubilization process is discussed in terms of solvent polarity and differential solid-state structure of racIB and SIB. The thermodynamic parameters for the solubilization process are presented.     

环糊精及其衍生物在药物分离分析中的应用进展

近年来,环糊精及其衍生物在药物尤其是手性药物分离分析中的应用受到了广泛关注。本文通过查阅有关文献,对CD及其衍生物在高效液相色谱、气相色谱、毛细管电泳色谱、薄层色谱、超,临界流体色谱、高速逆流色谱以及膜分离等方法中的应用作了系统介绍,具有十分重要的参考价值。     

Cyclodextrins as Supramolecular Recognition Systems: Applications in the Fabrication of Electrochemical Sensors

Supramolecular chemistry, although focused mainly on noncovalent intermolecular and intramolecular interactions, which are considerably weaker than covalent interactions, can be employed to fabricate sensors with a remarkable affinity for a target analyte. In this review the development of cyclodextrin-based electrochemical sensors is described and discussed. Following a short introduction to the general properties of cyclodextrins and their ability to form inclusion complexes, the cyclodextrin-based sensors are introduced. This includes the combination of cyclodextrins with reduced graphene oxide, carbon nanotubes, conducting polymers, enzymes and aptamers, and electropolymerized cyclodextrin films. The applications of these materials as chiral recognition agents and biosensors and in the electrochemical detection of environmental contaminants, biomolecules and amino acids, drugs and flavonoids are reviewed and compared. Based on the papers reviewed, it is clear that cyclodextrins are promising molecular recognition agents in the creation of electrochemical sensors, chiral sensors, and biosensors. Moreover, they have been combined with a host of materials to enhance the detection of the target analytes. Nevertheless, challenges remain, including the development of more robust methods for the integration of cyclodextrins into the sensing unit.     

Org 25969 (sugammadex), a selective relaxant binding agent for antagonism of prolonged rocuronium-induced neuromuscular block

Background. Org 25969 is a cyclodextrin compound designed toreverse a rocuronium-induced neuromuscular block. The aim ofthis study was to explore the efficacy, dose–responserelation and safety of Org 25969 for reversal of a prolongedrocuronium-induced neuromuscular block. Methods. Thirty anaesthetized adult patients received rocuronium0.6 mg kg^–1 as an initial dose followed by incrementsto maintain a deep block at a level of <10 PTCs (post-tetaniccounts) recorded every 6 min. Neuromuscular monitoring was carriedout using accelerometry, in a train-of-four (TOF) mode usingTOF-Watch®SX. At recovery of T₂, following at least 2 hof neuromuscular block, patients received their randomly assigneddose of 0.5, 1.0, 2.0, 4.0 or 6.0 mg kg^–1 of Org 25969.Anaesthesia and neuromuscular monitoring were continued fora minimum period of 30 min after Org 25969 administration. Themain end-point of the study was the time to achieve a sustainedrecovery of TOF ratio to 0.9. Patients were followed up for7 days after anaesthesia. Results. The results showed a dose-related decrease in the averagetime taken to attain a TOF ratio of 0.9 from 6:49 (min:s) withthe 0.5 mg kg^–1 dose to 1:22 with the 4.0 mg kg^–1dose. Weighted non-linear regression analysis showed the fastestachievable time to TOF ratio of 0.9 to be 1:35. Org 25969 producedno major adverse effects. Conclusion. Org 25969 effectively reversed a deep and prolongedneuromuscular block induced by rocuronium. The effective reversaldose appears to be 2–4 mg kg^–1.     

Linear cyclodextrin-containing polymers and their use as delivery agents

Cyclodextrins, cyclic oligomers of glucose, have been used in pharmaceutical formulations for decades as a result to their biocompatibilities, low toxicities and their abilities to solubilise organic small molecules via inclusion complex formation. The incorporation of cyclodextrins within polymers of numerous types, for use as drug delivery agents, has been explored. Illustrative of the flexibility in polymer chemistry and delivery application that is possible with these materials, two linear cyclodextrin-containing polymers are in preclinical and clinical development for the non-covalent delivery of nucleic acid therapeutics and covalent delivery of a small-molecule drug, respectively. This document provides an overview of the background and progress that has been made with these materials thus far, as well as suggestions for their future development and characterisation.     

Effect of Cyclodextrin Charge on Complexation of Neutral and Charged Substrates: Comparison of (SBE)7M-β-CD to HP-β-CD

Purpose. To understand the role of charge in substrate/cyclodextrin complexation by comparing the binding of neutral and charged substrates to a neutral cyclodextrin, such as hydroxypropyl –CD (HP––CD) with 3.5 degrees of substitution, and an anionically charged cyclodextrin, such as sulfobutyl ether –CD ((SBE)_7M––CD) with 6.8 degrees of substitution. Method. HP––CD and (SBE)_7M––CD were evaluated in their ability to form inclusion complexes with neutral compounds, as well as to cationic and anionic substrates in their charged and uncharged forms. The complexation constants (K_c) were determined via a UV spectrophotometric technique, by monitoring the change in substrate absorbance upon incremental addition of a concentrated cyclodextrin solution. The role of electrostatic interaction was probed by observing K_c as a function of solution ionic strength. Results. Neutral molecules displayed a stronger interaction with (SBE)_7M––CD compared to HP––CD. In those cases where the guest possessed a charge (positive or negative), HP––CD/substrate complexes exhibited a decrease in complexation strength (2 to 31 times lower) compared to the neutral forms of the same substrate. The same was true (but to a larger extent, 41 times lower) for negatively charged molecules binding to (SBE)_7M––CD due to charge–charge repulsion. However, positively charged molecules interacting with the negatively charged (SBE)_7M––CD displayed a similar binding capability as their neutral counterpart, due to charge–charge attraction. Further evaluation through manipulation of solution ionic strength revealed strong electrostatic interactions between substrate and cyclodextrin charges. In addition, the studies suggested that on average two sulfonates out of seven may be involved in forming ionic attraction or repulsion effects with the positive charges on prazosin and papaverine, or negative charges of ionized naproxen and warfarin. Conclusions. Presence of charge on the cyclodextrin structure provides an additional site of interaction compared to neutral cyclodextrins, which may be modified using solution ionic strength.