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Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Gerhard Gröbner)
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2011 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 409, no 1-2, 19-29 p.Article in journal (Refereed) Published
Abstract [en]

A method for the in situgelation of poloxamers and the mucoadhesive polymer chitosan has been developedby exploiting the tendency of poloxamer solution to form gel at physiological temperatures and of chitosan (CT) to form ionotropic gel structures in the presence of sodium tripolyphosphate (TPP). Novel poloxamer gels containing CT –TPP complex formed in situduring the administration were prepared bymixing poloxamer –CT and poloxamer–TPPsolutions in double syringes. The micellization and gelation ofpoloxamer 407 in the presence of chitosan and/or TPP were studied using differential scanning calorimetry and tube inversion; both additives were found to reduce the critical micellization temperature and critical gelation temperature of poloxamer aqueous solution. The poloxamer gels  ontaining CT –TPPcomplexformed in situwere found to exhibit reduced dissolution rate and superior release characteristicswith three different drugs –metoprolol, doxycycline and flufenamic acid. Furthermore, by varying thecompositions of the two solutions independently, it is possible to control the pH in a way to suit the solubilization of a drug as well as the specific environment of a particular application site. By varying the concentrations of chitosan, TPP and poloxamer, the delivery system can be fine-tuned to afford gels with specific properties, ranging from nanoparticle suspensions to semisolid gels. These in situgels have thepotential to increase the utility of thermo-reversible poloxamers in drug delivery

Place, publisher, year, edition, pages
Elsevier , 2011. Vol. 409, no 1-2, 19-29 p.
Keyword [en]
poloxamer gel, chitosan, drug delivery, micellization, in situ gelation, nanoparticle
National Category
Physical Chemistry
Research subject
Pharmaceutics
Identifiers
URN: urn:nbn:se:umu:diva-40488DOI: 10.1016/j.ijpharm.2011.02.017OAI: oai:DiVA.org:umu-40488DiVA: diva2:400159
Note
Available online 16 February 2011Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2017-12-11Bibliographically 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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