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Biomedical subjects

E Marttin

Publications and source records attributed to E Marttin.

10 recordsLinked to original sources
PubMed1999

Cyclodextrins in nasal drug delivery.

Nasal drug delivery is an attractive approach for the systemic delivery of high potency drugs with a low oral bioavailability due to extensive gastrointestinal breakdown and high hepatic first-pass effect. For lipophilic drugs nasal delivery is possible if they can be dissolved in the dosage form. Peptide and protein drugs often have a low nasal bioavailability because of their large size and hydrophilicity, resulting in poor transport properties across the nasal mucosa. Cyclodextrins are used to improve the nasal absorption of these drugs by increasing their aqueous solubility and/or by enhancing their nasal absorption. With several cyclodextrins very efficient nasal drug absorption has been reported, but also large interspecies differences have been found. Studies concerning the safety of cyclodextrins in nasal drug formulations demonstrate the non-toxicity of the cyclodextrins and also clinical data show no adverse effects. Therefore, some cyclodextrins can be expected to become effective and safe excipients in nasal drug delivery.

Journal Article↗
PubMed1999

The effect of methylated beta-cyclodextrins on the tight junctions of the rat nasal respiratory epithelium: electron microscopic and confocal laser scanning microscopic visualization studies.

The nasal absorption enhancer randomly methylated beta-cyclodextrin (RAMEB) is thought to increase the paracellular permeability of the nasal epithelium by opening of the tight junctions. The effects of RAMEB on the cytoskeleton of the rat nasal epithelium in vivo were determined by confocal laser scanning microscopy (CLSM). The effects on the tight junctions of the rat nasal epithelium were also investigated, using transmission electron microscopy (TEM) of thin sections. The effects of RAMEB were compared with those of the absorption enhancer sodium taurodihydrofusidate (STDHF). Fifteen minutes after nasal administration of 2% RAMEB in vivo, the distribution of cytoskeletal actin was comparable to the untreated control, suggesting that RAMEB does not cause opening of the tight junctions via cytoskeletal interactions. In contrast, administration of 1% STDHF resulted in changes in the actin staining. Furthermore, with TEM severe damage of the nasal epithelium was observed after treatment with 1% STDHF. Ultrastructural changes of the tight junctions were not apparent in TEM sections after treatment with 2% RAMEB. In conclusion, CLSM and TEM are suitable methods to visualize the effects of absorption enhancers on nasal epithelial morphology.

Actins↗
PubMed1998

Nasal mucociliary clearance as a factor in nasal drug delivery.

The nasal mucociliary clearance system transports the mucus layer that covers the nasal epithelium towards the nasopharynx by ciliary beating. Its function is to protect the respiratory system from damage by inhaled substances. Impairment of nasal mucociliary clearance can result in diseases of the upper airways. Therefore, it is important to study the effects of drugs and drug excipients on nasal mucociliary clearance. A large number of methods are used to assess mucociliary clearance. These methods study the effects of drug and excipients on the mucociliary system in vitro or in vivo in animals and humans. In some cases, the results of different in vitro and in vivo measurements do not correlate well. In vitro methods, especially ciliary beat frequency measurements, have been demonstrated to be valuable tools for toxicity screening. However, in vivo studies are essential to confirm the safety of nasal drug formulations. Nasal mucociliary clearance also has implications for nasal drug absorption. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in fast systemic drug absorption. Several approaches are discussed to increase the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. However, more experimental evidence is needed to support the conclusion that this improved absorption is caused by a longer residence time of the nasal drug formulation.

Journal Article↗
PubMed1998

Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs.

Cyclodextrins are used in nasal drug delivery as absorption enhancing compounds to increase the intranasal bioavailability of peptide and protein drugs. The most effective cyclodextrins in animal experiments are the methylated derivatives, dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin, which are active at low concentrations ranging between 2% and 5%. However, large species differences between rats, rabbits and humans exist for the nasal absorption enhancement by cyclodextrins. Based on toxicological studies of the local effects of cyclodextrins on the nasal mucosa dimethyl-beta-cyclodextrin and randomly methylated beta-cyclodextrin are considered safe nasal absorption enhancers. Their effects were quite similar to controls (physiological saline), but smaller than those of the preservative benzalkonium chloride in histological and ciliary beat frequency studies. In these studies, and in a study of the release of marker compounds after nasal administration, methylated beta-cyclodextrins were less toxic than sodium glycocholate, sodium taurodihydrofusidate, laureth-9 and L-alpha-phosphatidylcholine. Systemic toxicity after nasal cyclodextrin administration is not expected, because very low doses of cyclodextrins are administered and only very small amounts are absorbed. The mechanism of action of cyclodextrins may be explained by their interaction with the nasal epithelial membranes and their ability to transiently open tight junctions.

Absorption↗
PubMed1997

Simplified solid-phase extraction method for determination of dihydroergotamine in rabbit and human serum using high-performance liquid chromatography with fluorescence detection.

A rapid, selective and sensitive method for the determination of dihydroergotamine (DHE) in serum was developed. Dihydroergocristine (DHEC) was used as an internal standard. Human and rabbit serum samples were extracted using commercial solid-phase cyano (CN) columns. Proteins were washed from these columns with pure acetonitrile, resulting in clean extracts. Extracts were subsequently separated by HPLC in an isocratic way, using a reversed-phase C18 analytical column. Fluorometric detection was performed at excitation and emission wavelengths of 277 and 348 nm, respectively. Calibration curves with amounts of DHE ranging from 2 to 32 ng, were linear. The limit of detection found for DHE was 0.2 ng, extracted from 0.5 ml rabbit or from 2.5 ml human serum. The limit of quantification in serum of both species was 0.7 ng. The method has been shown to be suitable for monitoring DHE in serum during pharmacokinetic studies in rabbits.

Analgesics, Non-Narcotic↗
PubMed1997

Nasal absorption of dihydroergotamine from liquid and powder formulations in rabbits.

Nasal drug delivery is an interesting route of administration for dihydroergotamine in migraine therapy. The currently available formulation contains dihydroergotamine at 4 mg/mL. For a nasal dose of 2 mg, a volume of 0.5 mL has to be administered, which sometimes leads to spillage of the formulation. The aim of the present study was to develop a nasal spray with a dihydroergotamine concentration of 10 mg/mL. To increase the solubility and stability of dihydroergotamine, randomly methylated beta-cyclodextrin was used. Liquid formulations and lyophilized powders of dihydroergotamine and randomly methylated beta-cyclodextrin were prepared. The liquid and powder formulations were compared by determining their pharmacokinetics and absolute bioavailability after nasal administration in rabbits. Nasal sprays were significantly more effective than drops in increasing the nasal bioavailability of dihydroergotamine, but the amount of randomly methylated beta-cyclodextrin in liquid sprays did not significantly alter the nasal absorption. For powder formulations, the dihydroergotamine absorption was dependent on the amount of methylated beta-cyclodextrin and powder volume, and the nasal bioavailability from the optimal powder was slightly, but not significantly, higher than that for liquids. In conclusion, the formulations investigated are a substantial improvement of the current commercial formulation, not only because the spray volume of the liquid spray can be reduced 2.5 times, but also because of the increased stability of liquid and powder sprays with randomly methylated-beta-cyclodextrin.

Absorption↗
PubMed1997

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 vivo using confocal laser scanning microscopy. Furthermore, the influence of nasal absorption enhancers (randomly methylated beta-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 beta-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 beta-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↗
PubMed1996

A critical comparison of methods to quantify stratum corneum removed by tape stripping.

Skin surface stripping with adhesive tape has been used to study the barrier function of the stratum corneum. Usually, the amount of stratum corneum removed by stripping is not linearly proportional to the number of strips removed. The generally accepted quantitative method to determine the amount of stratum corneum material on a tape strip is weighing. This method however has certain drawbacks, it is time consuming and laborious because tape strips have to be weighed twice and sometimes it cannot be used to determine concentration profiles in the skin of active substances in topically applied vehicles. In this paper, the accuracy and reliability of an alternative method to determine the amount of stratum corneum removed by tape stripping of the skin was investigated and compared to weighing. It is based on the spectrophotometric examination of the tape. The light absorption by the proteins on the tape is correlated to the weight of the stratum corneum material. This method was found to be easier and faster than weighing, but it was less reliable because the light scattering of the stratum corneum on the tape largely overshadowed the absorption of the proteins. The light scattering showed a linear increase with an increasing amount of material on the tape, but with a large variability, resulting in calibration curves with correlations of 0.8400. However, direct spectroscopic analysis of stratum corneum tape strips has some distinct advantages even if it cannot be used for the exact quantification of stratum corneum proteins. With direct spectroscopic measurements, a tape strip can be laterally examined to inspect its homogeneity. Direct spectroscopic measurements on tape strips might also be employed to investigate the lateral and in-depth distribution of strongly light-absorbing substances in the stratum corneum.

Adhesives↗
PubMed1995

Effects of absorption enhancers on rat nasal epithelium in vivo: release of marker compounds in the nasal cavity.

PURPOSE: The assessment of the effects of nasal absorption enhancers on the rat nasal epithelium and membrane permeability in vivo after a single nasal dose of the enhancers. METHODS: The release of marker compounds (protein, cholesterol and acid phosphatase) from the nasal epithelium was measured using a lavage technique. The nasal membrane permeability was determined after intravenous administration of a systemic tracer (FITC-albumin). RESULTS: The effects of the absorption enhancers could be classified into four categories. The first consisted of HP beta CD (5%), DM beta CD (2%) and RAMEB (2%) and was not different from the control (physiological saline). For the second category, DM beta CD (5%), effects were significantly higher than for the control. The third category, SGC (1%), was more active than DM beta CD (5%) but less active than the last group. The fourth, most membrane damaging, category consisted of STDHF (1%), laureth-9 (1%) and LPC (1%). Administration of these three enhancers also resulted in release of acid phosphatase, indicating that severe membrane damage occurred. The release of cholesterol from nasal epithelium was largely dependent on the cholesterol solubilisation of the absorption enhancers. The amount of cholesterol released by laureth-9 and LPC was the largest. CONCLUSIONS: The results of this in vivo study are in agreement (i.e. similarity in rank order) with morphological and ciliotoxicity studies of nasal absorption enhancers, demonstrating that this in vivo model is a valuable tool to classify nasal absorption enhancers according to their effects on the rat nasal epithelium.

Absorption↗