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  • 1. Alhayali, Amani
    et al.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Velaga, Sitaram
    Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 79-88Article in journal (Refereed)
    Abstract [en]

    The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work.

    Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions.

    All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures.

    Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.

  • 2. Filippov, Andrey
    et al.
    Munavirov, Bulat
    Sparrman, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ishmuhametova, Valentina
    Rudakova, Maya
    Shriram, Prashant
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Interaction of a poly(acrylic acid) oligomer with dimyristoylphosphatidylcholine bilayers2011In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 7, p. 3754-3761Article in journal (Refereed)
    Abstract [en]

    We studied the influence of 5 kDa poly(acrylic acid) (PAA) on the phase state, thermal properties, and lateral diffusion in bilayered systems of dimyristoylphosphatidylcholine (DMPC) using (31)P NMR spectroscopy, differential scanning calorimetry (DSC), (1)H NMR with a pulsed field gradient, and (1)H nuclear Overhauser enhancement spectroscopy (NOESY). The presence of PAA does not change the lamellar structure of the system. (1)H MAS NOESY cross-peaks observed for the interaction between lipid headgroups and polyion protons demonstrated only surface PAA-biomembrane interaction. Small concentrations of PAA (up to ∼4 mol %) lead to the appearance of a new lateral phase with a higher main transition temperature, a lower cooperativity, and a lower enthalpy of transition. Higher concentrations lead to the disappearance of measurable thermal effects. The lateral diffusion coefficient of DMPC and the apparent activation energy of diffusion gradually decreased at PAA concentrations up to around 4 mol %. The observed effects were explained by the formation of at least two types of PAA-DMPC lateral complexes as has been described earlier (Fujiwara, M.; Grubbs, R. H.; Baldeschwieler, J. D. J. Colloid Interface Sci., 1997, 185, 210). The first one is characterized by a stoichiometry of around 28 lipids per polymer, which corresponds to the adsorption of the entire PAA molecule onto the membrane. Lipid molecules of the complex are exchanged with the "pure" lipid bilayer, with the lifetime of the complex being less than 0.1 s. The second type of DMPC-PAA complex is characterized by a stoichiometry of 6 to 7 lipids per polymer and contains PAA molecules that are only partially adsorbed onto the membrane. A decrease in the DMPC diffusion coefficient and activation energy for diffusion in the presence of PAA was explained by the formation of a new cooperative unit for diffusion, which contains the PAA molecule and several molecules of lipids.

  • 3.
    Rosenbaum, Erik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Johansson, Lennart B-Å
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A characterisation study on the application of inverted lyotropic phases for subcutaneous drug release2010In: International journal of pharmaceutics, ISSN 1873-3476, Vol. 388, no 1-2, p. 52-7Article in journal (Refereed)
    Abstract [en]

    An experimental characterisation of lipid mixtures consisting of inverted hexagonal and inverted cubic phases composed of soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO) was performed. The release of five chromophores of varying lipophilicity, used as model drugs, was investigated. Two experimental setups were applied: one based on maintaining sink condition, while a constant volume release medium was employed for the other. For neither setup, no correlation between the model drug lipophilicity and the polarity of the carrier matrix was found. However, the lipid phases showed a prolonged release, spanning weeks, of the model drugs, which exhibit lipophilicity values ranging by four orders of magnitude.

  • 4.
    Ur-Rehman, Tofeeq
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels2011In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 409, no 1-2, p. 19-29Article in journal (Refereed)
    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

  • 5.
    Ur-Rehman, Tofeeq
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Effect of alginate, ethanol and CaCl2 on micellization and gelation of poloxamer 407 aqueous solutionManuscript (preprint) (Other academic)
  • 6.
    Ur-Rehman, Tofeeq
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Effect of DMSO on micellization, gelation and drug release profile of poloxamer 4072010In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 394, no 1-2, p. 92-98Article in journal (Refereed)
    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).

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