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Browsing by Subject "permeability"

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  • Hot-melt extrudated Indomethacin and polymer combinations and their permeability 
    Micklin, Maria (2022)
    Indomethacin is in a BCS-classification class two drug, meaning it has poor solubility but good permeability. Because of this solubility is a limiting factor for it reaching bloodcirculation. Amorphous form has better solubility than crystalline form. Most common problems with amorphous form are poor stability and process technical problems. In this study Indomethacin was combined with two different kind of polymers that were prepared by hot-melt extrusion. By hot-melt extrusion we can get more stable product than pure amorphous drug. These polymers were polyvinylpyrrolidone (PVPK179 and polyvinylpyrrolidonevinylacetate (PVPVA). They were prepared with Indomethacin 1:1 mass ratio. The aim was to study these extrudates and their stability, cumulative release and especially permeability. By using differential scanning calorimetry, X-ray diffraction and polarized light microscopy it was possible to analyze whether the drug was amorphous or crystalline. In the study it was found that by using hot-melt extrusion it was possible to make amorphous combinations of Indomethacin and polymers. Their permeability was between crystalline and amorphous form. PVPK17-Indomethacin combination had better permeability than PVPVA-Indomethacin combination. On the other hand PVPVA-Indomethacin had better cumulative release than PVPK17-Indomethacin combination
  • Lääkeaineiden luokittelu biofarmaseuttisten luokittelujärjestelmien mukaan, tapausesimerkki hydroklooritiatsidi 
    Saarikko, Elina (2010)
    Biopharmaceutical Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption. For a BCS biowaiver, the in vitro dissolution study may be used as a surrogate for in vivo bioequivalence studies. Currently, BCS I drugs are accepted as biowaiver candidates by EMEA, FDA and WHO. EMEA and WHO also accept class III drugs in some conditions. The main difficulty in classifying drugs according to BCS is the determination of permeability. Biopharmaceutics Drug Distribution Classification System (BDDCS) was introduced to provide a surrogate for permeability. If the major route of elimination is metabolism, then the drug exhibites high permeability. There are two parts in this master thesis. BCS and BDDCS are discussed and evaluated in the literature part. The focus is in the BCS III drugs. The purpose of the experimental part is to evaluate BCS III drug, hydrochlorothiazide as a biowaiver candidate. Solubility of the drug substance and dissolution of the drug product was determined. Aim of the permeability studies with Caco-2 cells were to study if hydrochlorothiazide permeates by passive diffusion across the monolayer. Importance of paracellular diffusion was evaluated by opening tight junctions with EDTA. Influence of dissolution rate was evaluated by theoretical simulation. According to the results of this study, hydrochlorothiazide has good solubility in aqueous buffer. It has been reported to diffuse passively across the epithelial cells but in this study permeability increased when concentration decreased. This may be due to active transport. Hydrochlorothiazide diffuses partially through the tight junctions. Dissolution of the hydrochlrothiazide tablet was very rapid. Drug eliminates almost entirely by metabolism, it is also BDDCS class III drug. EMEA and WHO accept BCS III drugs as biowaiver candidate if dissolution rate is very rapid. According to this, hydrochlorothiazide could be suggested as a biowaiver candidate. There are also other issues to be considered, for example excipients used in tablets. Since hydrochlorothiazide has been discovered to be absorbed in the upper part of the small intestine, the influence of excipients is especially important. This possible influence should be evaluated before the final decision of biowaiver.
  • Sarveiskalvon permeabiliteetin ennustaminen QSPR-mallin avulla 
    Tissari, Anita (2011)
    QSPR (Quantitive structure property relationship) describes relationship between descriptors and biological activity. Therefore, QSPR models are useful tools in drug discovery. The literature review summarizes existing corneal, intestinal and blood brain barrier permeability models. The most common descriptors are hydrophobicity, polar surface and H-bonding capability. Also, the size of molecule may have influence on permeability even though the results are sometimes contradictory. Descriptors might have limiting values such as those presented in Lipinski's ‖rule of five‖. Drug candidate should not have 'rule of 5' values outside of the useful range, otherwise the per oral absorption of the compound may be compromised. In the literature review the transporter activity in cornea, intestine and blood brain barrier is described. Currently, many QSPR-models have been developed to predict interactions of drug candidates with transporters. The purpose of experimental part was to build in silico -model of corneal passive permeability for early ocular drug discovery. QSPR-model was built using permeability data and molecular descriptors of 54 molecules. Corneal permeability coefficients in rabbits were obtained from the literature. Octanol-water partitition coefficient at pH 7,4 (logD) and the total number of hydrogen bonds were the descriptors in the final model. The final equation was log(permeability coefficient) = -3,96791 - 0,177842*Htotal + 0,311963*logD(pH7,4). For this model R2 was 0,77 ja Q2 was 0,75. The model was evaluated using an external data set of 15 compounds and by pharmacokinetic modeling. Predicted permeability coefficients were used to simulate the aqueous humour concentrations of sevent compounds at steady-state. In addition corneal absorption coefficient (Kc) was simulated for 13 compounds and these values were compared to predicted permeability. The predicted permeability coefficients correlated well with experimental permeability coefficients. In addition aqueous humour concentrations can be simulated in steady state using predicted (QSPR) permeability coefficients. The final QSPR-model may be used in ocular drug discovery and development.

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