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Browsing by Subject "itraconazole"

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  • Mikkonen, Heidi (2014)
    One way to improve the solubility of a poorly-water-soluble drug is to make amorphous solid dispersion of it with one or several carrier polymers. However, the amorphous solid dispersions are often unstable. Stability and amorphisation of drug substance depend on e.g. the miscibility of the components in dispersion. Moreover, in the early stage of drug development there is available only limited amount of active substance and time to the analyses. In this study, the primary goal was to develop a method combining the preparing (solvent method) and the analyzing (MTDSC, modulated temperature differential scanning calorimetry) methods. In the method developing part, the possible effect of analyzing parameters of MTDSC to the results was also tested. Amorphous solid dispersions were prepared and analyzed with the invented method. The dispersions were made of poorly-watersoluble itraconazole with hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and/or polyvinylpyrrolidone (PVP K30). X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) were also used to make the interpretation of results easier and more reliable. By analyzing the prepared dispersions the differences in the miscibilities of the used polymers with itraconazole were examined and it was also studied how the miscibility affected to the amorphicity of the prepared dispersion. As a secondary goal, it was tested if combining the two polymers would improve the miscibility and amorphicity of the prepared dispersion. In many cases, with the developed method it was possible to make mixed and amorphous solid dispersion with 10-20 % itraconazole concentration. Used small amount of drug was roughly enough to the detection limit of the used analyzing techniques. The analyzing parameters of MTDSC were not seen to affect to the results in this study which makes the use of this method easier. The results of used analyses were in some part contradictory and that is why it is recommended to use several analyzing techniques or methods that combine different kinds of techniques. In the study, it was seen that in the most part of the prepared dispersions there was more HPMC-AS than PVP K30. This was speculated to be caused by the ionic bonds between the basic itraconazole molecules and acidic succinyl groups in HPMC-ASs and also because of more hygroscopic nature of PVP K30 which increases mobility which in turn increases probability of collision of itraconazole molecules. The use of two polymers in the same time was useful especially in the case of 90/10 HPMC-AS/PVP K30 polymer ratio. This was speculated to be caused by different vaporization rates of the used solvents (DCM and methanol) and too slow evaporation phase. To explain and examine this observation more thoroughly, nuclear magnetic resonance (NMR) -measurements were done. When analyzing the prepared dispersions and itraconazole alone, it was observed that with used amorphisation method (solvent method) itraconazole was in a form that differs from the original polymorph. This form of itraconazole was probably some kind of liquid crystal and was examined further by heating the sample and analyzing it by XRPD. Although there are some other studies to support this hypothesis, this interpretation needs some confirmatory analyses with other methods: with high temperature SAXS (small angle X-ray scattering) and NMR.
  • Kinnari, Päivi (2010)
    Most new drug molecules discovered today suffer from poor bioavailability. Poor oral bioavailability results mainly from poor dissolution properties of hydrophobic drug molecules, because the drug dissolution is often the rate-limiting event of the drug's absorption through the intestinal wall into the systemic circulation. During the last few years, the use of mesoporous silica and silicon particles as oral drug delivery vehicles has been widely studied, and there have been promising results of their suitability to enhance the physicochemical properties of poorly soluble drug molecules. Mesoporous silica and silicon particles can be used to enhance the solubility and dissolution rate of a drug by incorporating the drug inside the pores, which are only a few times larger than the drug molecules, and thus, breaking the crystalline structure into a disordered, amorphous form with better dissolution properties. Also, the high surface area of the mesoporous particles improves the dissolution rate of the incorporated drug. In addition, the mesoporous materials can also enhance the permeability of large, hydrophilic drug substances across biological barriers. T he loading process of drugs into silica and silicon mesopores is mainly based on the adsorption of drug molecules from a loading solution into the silica or silicon pore walls. There are several factors that affect the loading process: the surface area, the pore size, the total pore volume, the pore geometry and surface chemistry of the mesoporous material, as well as the chemical nature of the drugs and the solvents. Furthermore, both the pore and the surface structure of the particles also affect the drug release kinetics. In this study, the loading of itraconazole into mesoporous silica (Syloid AL-1 and Syloid 244) and silicon (TOPSi and TCPSi) microparticles was studied, as well as the release of itraconazole from the microparticles and its stability after loading. Itraconazole was selected for this study because of its highly hydrophobic and poorly soluble nature. Different mesoporous materials with different surface structures, pore volumes and surface areas were selected in order to evaluate the structural effect of the particles on the loading degree and dissolution behaviour of the drug using different loading parameters. The loaded particles were characterized with various analytical methods, and the drug release from the particles was assessed by in vitro dissolution tests. The results showed that the loaded drug was apparently in amorphous form after loading, and that the loading process did not alter the chemical structure of the silica or silicon surface. Both the mesoporous silica and silicon microparticles enhanced the solubility and dissolution rate of itraconazole. Moreover, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. Finally, the mesoporous silicon particles loaded with itraconazole were found to be unstable under stressed conditions (at 38 qC and 70 % relative humidity).
  • Toppari, Antti (2011)
    Nowadays growing number of new active pharmaceutical ingredients (API) have large molecular weight and are hydrophobic. The energy of their crystal lattice is bigger and polarity has decreased. This leads to weakened solubility and dissolution rate of the drug. These properties can be enhanced for example by amorphization. Amorphous form has the best dissolution rate in the solid state. In the amorphous form drug molecules are randomly arranged, so the energy required to dissolve molecules is lower compared to the crystalline counterpart. The disadvantage of amorphous form is that it is unstable. Amorphous form tends to crystallize. Stability of amorphous form can be enhanced by adding an adjuvant to drug product. Adjuvant is usually a polymer. Polymers prevent crystallization both by forming bonds with API molecules and by steric hindrance. The key thing in stabilizing amorphous form is good miscibility between API and polymer. They have to be mixed in a molecular level so that the polymer is able to prevent crystallization. The aim of this work was to study miscibility of drug and polymer and stability of their dispersion with different analytical methods. Amorphous dispersions were made by rotary evaporator and freeze dryer. Amorphicity was confirmed with X-ray powder diffraction (XRPD) right after preparation. Itraconazole and theophylline were the chosen molecules to be stabilized. Itraconazole was expected to be easier and theophylline more difficult to stabilize. Itraconazole was stabilized with HPMC and theophylline was stabilized with PVP. Miscibility was studied with XRPD and differential scanning calorimetry (DSC). In addition it was studied with polarized light microscope if miscibility was possible to see visually. Dispersions were kept in stressed conditions and the crystallization was analyzed with XRPD. Stability was also examined with isothermal microcalorimetry (IMC). The dispersion of itraconazole and theophylline 40/60 (w/w) was completely miscible. It was proved by linear combination of XRPD results and single glass transition temperature in DSC. Homogenic well mixed film was observed with light microscope. Phase separation was observed with other compositions. Dispersions of theophylline and PVP mixed only partly. Stability of itraconazole dispersions were better than theophylline dispersions which were mixed poorer. So miscibility was important thing considering stability. The results from isothermal microcalorimetry were similar to results from conventional stability studies. Complementary analytical methods should be used when studying miscibility so that the results are more reliable. Light microscope is one method in addition to mostly used XRPD and DSC. Analyzing light microscope photos is quite subjective but it gives an idea of miscibility. Isothermal microcalorimetry can be one option for conventional stability studies. If right conditions can be made where the crystallization is not too fast, it may be possible to predict stability with isothermal microcalorimetry.