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The in vitro transport of dihydroergotamine across porcine nasal respiratory and olfactory mucosa and the effect of a novel powder formulation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2007 (English)In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 17, no 4, 267-271 p.Article in journal (Refereed) Published
Abstract [en]

The objective was to investigate the transport of dihydroergotamine (DHE) across porcine nasal respiratory and olfactory mucosa and to evaluate the absorption enhancing effect of a novel dry powder formulation compared with a reference solution with the horizontal Ussing chamber method. The powder formulation was obtained by mixing micronized DHE particles and mucoadhesive carrier particles (sodium starch glycolate) to create an interactive mixture. The horizontal Ussing chamber method was chosen as the in vitro model since it provides the opportunity to apply a dry powder formulation and compare the transport across the two types of nasal mucosa. A histological evaluation confirmed that the mucosa had been correctly isolated. The results showed no significant difference in the absorption from the powder formulation compared with the reference solution, but the transport of DHE was significantly higher across olfactory mucosa than across respiratory mucosa. This may be explained by facilitated transport through paracellular transfer along the olfactory nerve cells.

Place, publisher, year, edition, pages
2007. Vol. 17, no 4, 267-271 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97563ISI: 000250032200006OAI: oai:DiVA.org:uu-97563DiVA: diva2:172558
Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2011-01-22Bibliographically approved
In thesis
1. Studies on a Novel Powder Formulation for Nasal Drug Delivery
Open this publication in new window or tab >>Studies on a Novel Powder Formulation for Nasal Drug Delivery
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nasal administration has potential for the treatment of indications requiring a fast onset of effect or for drugs with low oral bioavailability. Liquid nasal sprays are relatively common, but can be associated with suboptimal absorption from the nasal cavity; this thesis shows that nasal absorption can be significantly enhanced with a dry powder formulation.

It was shown that interactive mixtures, consisting of fine drug particles adhered to the surface of mucoadhesive carrier particles, could be created in a particle size suitable for nasal administration. Sodium starch glycolate (SSG), a common tablet excipient, was used as carrier material. In vitro evaluation of the formulation indicated that the mucoadhesion of the carrier was unlikely to be affected by the addition of a drug. The powder formulation did not improve the in vitro transfer of dihydroergotamine across porcine nasal mucosa compared with a liquid formulation; however, the results were associated with methodological shortcomings. The binding of model substances to SSG and three other excipients was evaluated. Ion exchange interactions were for example detected between SSG and cationic drugs, but these interactions were most extensive at low salt concentrations and should unlikely affect in vivo bioavailability at physiological salt concentrations. Absorption of the peptide drug desmopressin from the SSG nasal formulation, from a novel sublingual tablet formulation and from a commercial nasal liquid spray was evaluated in a clinical trial. While no improvement over the liquid spray was seen with the sublingual tablet, plasma concentrations after the nasal powder formulation were three times higher than those after the liquid spray. All formulations were well accepted by the volunteers. The use of currently available mucoadhesive carrier particles in interactive mixtures offers potential for a new method of producing nasal powder formulations that should also be applicable to large scale production.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 81
Keyword
nasal drug delivery, nasal powder spray, interactive mixture, mucoadhesion, sodium starch glycolate, superdisintegrant, bioavailability, clinical trial
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-9292 (URN)978-91-554-7288-7 (ISBN)
Public defence
2008-10-24, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2008-10-03 Created: 2008-10-03 Last updated: 2009-05-06Bibliographically approved
2. Olfactory Transfer of Analgesic Drugs After Nasal Administration
Open this publication in new window or tab >>Olfactory Transfer of Analgesic Drugs After Nasal Administration
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa.

In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography.

In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo.

In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 55
Keyword
Pharmaceutics, Nasal administration, Olfactory transfer, Olfactory pathways, Central nervous system, Blood-brain barrier, Nasal respiratory mucosa, Olfactory mucosa, Olfactory bulb, Horizontal Ussing chamber, Morphine, Dihydroergotamine, Rat, Mouse, Swine, Autoradiography, Viability, Powder formulations, Galenisk farmaci
Identifiers
urn:nbn:se:uu:diva-7829 (URN)978-91-554-6871-2 (ISBN)
Public defence
2007-05-11, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2010-03-23Bibliographically approved

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Fransén, NellyBjörk, Erik

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