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Controlled release gel formulations and preclinical screening of drug candidates
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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 [en]
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: urn:nbn:se:umu:diva-40489ISBN: 978-91-7459-161-3OAI: oai:DiVA.org:umu-40489DiVA: diva2:400163
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
List of papers
1. Effect of DMSO on micellization, gelation and drug release profile of poloxamer 407
Open this publication in new window or tab >>Effect of DMSO on micellization, gelation and drug release profile of poloxamer 407
2010 (English)In: Internation Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 394, no 1-2, 92-98 p.Article in journal (Refereed) Published
Abstract [en]

The application of many recently developed or approved drugs and pharmaceuticals is seriously hampered by their low solubility in aqueous media. Hence, numerous promising pharmaceutical delivery systems (including novel "smart" systems based on poloxamer gels, which have highly advantageous thermo-reversible characteristics and low toxicity) cannot solubilize required doses of various drugs without additives such as co-solvents or salts. Therefore, we have studied the effects of dimethyl sulphoxide (DMSO)-a commonly used co-solvent during drug development stages-on the micellization, gelation and dissolution properties of aqueous poloxamer solutions. Differential scanning calorimetry and tube inversion experiments clearly showed that DMSO induces reductions in the critical micellization and gelation temperatures of poloxamer systems. In addition, high resolution solid state 1H Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses provided indications of the specific chemical groups in the poloxamer affected by DMSO, and the molecular mechanism involved. The presence of DMSO accelerated dissolution of the pure gel in water and the release of a hydrophobic drug (flufenamic acid) from poloxamer gel, while it reduced the release of a hydrophilic drug (metoprolol tartrate).

Place, publisher, year, edition, pages
Elsevier B.V., 2010
Keyword
Poloxamer, Drug delivery, Micellization, DMSO, Calorimetry, NMR
Identifiers
urn:nbn:se:umu:diva-34638 (URN)10.1016/j.ijpharm.2010.05.012 (DOI)000279720400011 ()20472044 (PubMedID)
Available from: 2010-06-10 Created: 2010-06-10 Last updated: 2011-04-08Bibliographically approved
2. Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels
Open this publication in new window or tab >>Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels
2011 (English)In: Internation 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
Keyword
poloxamer gel, chitosan, drug delivery, micellization, in situ gelation, nanoparticle
National Category
Physical Chemistry
Research subject
Pharmaceutics
Identifiers
urn:nbn:se:umu:diva-40488 (URN)10.1016/j.ijpharm.2011.02.017 (DOI)
Note
Available online 16 February 2011Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2012-06-26Bibliographically approved
3. Effect of alginate, ethanol and CaCl2 on micellization and gelation of poloxamer 407 aqueous solution
Open this publication in new window or tab >>Effect of alginate, ethanol and CaCl2 on micellization and gelation of poloxamer 407 aqueous solution
(English)Manuscript (preprint) (Other academic)
Keyword
Poloxamer, In situ gels, calorimetry, alginate
National Category
Physical Chemistry
Research subject
Pharmaceutics
Identifiers
urn:nbn:se:umu:diva-40484 (URN)
Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2011-03-01Bibliographically approved
4. Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion
Open this publication in new window or tab >>Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion
(English)Manuscript (preprint) (Other academic)
Keyword
Type III secretion inhibitors, pharmacokintics, anti-chlamydial activity, salicylidene acylhdrazides, preclinical screening
National Category
Medicinal Chemistry
Research subject
Pharmaceutics; Pharmaceutical Microbiology
Identifiers
urn:nbn:se:umu:diva-40485 (URN)
Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2011-03-01Bibliographically approved
5. Preliminary pharmacokinetics of the bacterial virulence inhibitor N'-(3,5-dibromo-2-hydroxy-benzylidenene)-nicotinic acid hydrazide
Open this publication in new window or tab >>Preliminary pharmacokinetics of the bacterial virulence inhibitor N'-(3,5-dibromo-2-hydroxy-benzylidenene)-nicotinic acid hydrazide
Show others...
2012 (English)In: Advances in Yersinia Research, Springer, 2012, 349-356 p.Chapter in book (Other academic)
Abstract [en]

Bacterial virulence inhibitors are potential novel drugs that may be used to treat infections. N′-(3,5-dibromo-2-hydroxy-benzylidene)-nicotinic acid hydrazide, ME0052, has been shown to inhibit type III secretion (T3S) and virulence in several Gram-negative enteric pathogens including Yersinia pseudotuberculosis. In vitro data suggest that ME0052 may be developed into drugs against bacterial gastroenteritis. Here we describe preliminary pharmacokinetics of ME0052 after intraperitoneal and subcutaneous administration in mice. The aim of this work was to identify suitable formulations and to determine pharmacokinetic parameters prior to testing in animal infection models. Peak plasma concentrations above the IC50 for virulence inhibition were achieved with high dose formulations and the elimination half-life was prolonged from 0.5 to 3.4 h using a poloxamer 407-based slow-release formulation.

Place, publisher, year, edition, pages
Springer, 2012
Series
, Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 954
Keyword
salicylidene acylhydrazide, pharmacokinetics, preclinical testing, sustained release formulations, anti-chlamydial activity
National Category
Medicinal Chemistry Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Pharmaceutical Microbiology; Pharmaceutics
Identifiers
urn:nbn:se:umu:diva-40486 (URN)10.1007/978-1-4614-3561-7_42 (DOI)000333327900043 ()978-1-4614-3560-0 (ISBN)978-1-4614-3561-7 (ISBN)
Note

Originally published in thesis in manuscript form with the title: "Preliminary pharmacokinetics of the bacterial virulence inhibitor 3,5-dibromo-2-hydroxy-benzylidene nicotinic acid hydrazide"

Available from: 2011-02-24 Created: 2011-02-23 Last updated: 2015-06-10Bibliographically approved

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