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Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Gerhard Gröbner)
Discovery Drug Metabolism, Pharmacokinetics, and Bioanalysis, AstraZeneca R&D Lund, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
(English)Manuscript (preprint) (Other academic)
Keyword [en]
Type III secretion inhibitors, pharmacokintics, anti-chlamydial activity, salicylidene acylhdrazides, preclinical screening
National Category
Medicinal Chemistry
Research subject
Pharmaceutics; Pharmaceutical Microbiology
Identifiers
URN: urn:nbn:se:umu:diva-40485OAI: oai:DiVA.org:umu-40485DiVA: diva2:400153
Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2011-03-01Bibliographically approved
In thesis
1. Controlled release gel formulations and preclinical screening of drug candidates
Open this publication in new window or tab >>Controlled release gel formulations and preclinical screening of drug candidates
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Simple gel formulations may be applied to enhance the systemic and local exposure of potential compounds. The aim of this thesis is the development and characterization of controlled release formulations based on thermo-reversible poloxamer gels, which are suitable for novel drug delivery applications.  In particular co-solvents (DMSO, ethanol), mucoadhesive polymers (chitosan, alginate) and salts (sodium tripolyphosphate, CaCl2) have been used to enhance the applications of poloxamer 407 (P407) formulations in preclinical animal studies. The impact of these additives on the micellization and gelation properties of P407 aqueous solutions was studied by calorimetric methods, nuclear magnetic resonance spectroscopy (NMR) and “tube inversion” experiments. The drug release behavior of hydrophobic and hydrophilic drugs was characterized by using a membrane/membrane-free experimental setup. Finally, preliminary pharmacokinetic studies using a mouse model were conducted for screening of selected inhibitors of bacterial type III secretion and for evaluation of different formulations including P407 gel. All additives, used here, reduced the CMTs (critical micelle temperature) of dilute P407 solutions, with the exception of ethanol. The gelation temperature of concentrated P407 solutions was lowered in the presence of CaCl2, DMSO, TPP and alginate. 1H MAS (Magic Angle Spinning) NMR studies revealed that DMSO influences the hydrophobicity of the PPO segment of P407 polymers. Low concentrations of DMSO did not show any major effect on the drug release from P407 gels and may be used to improve the exposure of lead compounds in poloxamer gels. A newly developed in situ ionotropic gelation of chitosan in combination with TPP in P407 gels showed an enhanced resistance to water and reduced the release rates of model drugs. From preliminary pharmacokinetic studies in mice it was revealed that poloxamer formulations resulted in an increased plasma half-life of the lead compound.

Place, publisher, year, edition, pages
Umeå: Department of Chemistry, 2011. 51 p.
Keyword
poloxamer, drug delivery, micellization, DMSO, calorimetry, NMR. in situ gelation, chitosan, preclinical pharmacokinetics, type III secretion inhibitors
National Category
Physical Chemistry
Research subject
Pharmaceutics
Identifiers
urn:nbn:se:umu:diva-40489 (URN)978-91-7459-161-3 (ISBN)
Public defence
2011-03-22, KBC-huset, KB3A9, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2011-03-01 Created: 2011-02-23 Last updated: 2011-03-01Bibliographically approved

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Ur-Rehman, TofeeqElofsson, MikaelGylfe, Åsa

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CiteExportLink to record
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Citation style
  • apa
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