The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development

Useimmat uudet lääkeaineet ovat heikosti liukenevia ja lääkeaineen määrä lääkekehityksessä on hyvin rajallinen. Sen vuoksi on tarve löytää uusia liukoisuutta parantavia formulaatioita ja pienen mittakaavan metodeja ja malleja niiden tutkimiseen. Lääkekehitys on hyödyntänyt eläinkokeita lääkeaineiden...

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Main Author: Hiidenhovi, Sara
Other Authors: Matemaattis-luonnontieteellinen tiedekunta, Faculty of Sciences, Kemian laitos, Department of Chemistry, Jyväskylän yliopisto, University of Jyväskylä
Format: Master's thesis
Language:eng
Published: 2022
Subjects:
Online Access: https://jyx.jyu.fi/handle/123456789/82040
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author Hiidenhovi, Sara
author2 Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Kemian laitos Department of Chemistry Jyväskylän yliopisto University of Jyväskylä
author_facet Hiidenhovi, Sara Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Kemian laitos Department of Chemistry Jyväskylän yliopisto University of Jyväskylä Hiidenhovi, Sara Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Kemian laitos Department of Chemistry Jyväskylän yliopisto University of Jyväskylä
author_sort Hiidenhovi, Sara
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description Useimmat uudet lääkeaineet ovat heikosti liukenevia ja lääkeaineen määrä lääkekehityksessä on hyvin rajallinen. Sen vuoksi on tarve löytää uusia liukoisuutta parantavia formulaatioita ja pienen mittakaavan metodeja ja malleja niiden tutkimiseen. Lääkekehitys on hyödyntänyt eläinkokeita lääkeaineiden in vivo -käyttäytymisen tutkimiseen järjestelemällä eri formulaatioita paremmuusjärjestykseen perustuen niiden in vivo -olosuhteissa liuottamaan lääkeaineen määrään. Näitä järjestyksiä voidaan verrata in vitro -tuloksiin, jotka saadaan pienen mittakavaan dissoluutio-permeaatiomallin mittauksista. Tutkimuksen tavoitteena oli tutkia kokeellisten olosuhteiden vaikutusta pienen mittakavaan dissoluutio-permeaatiomallin toimivuuteen lääkekehityksessä. Lisäksi haluttiin tutkia kykeneekö tutkittava in vitro -malli tehokkaasti mallintamaan rotan in vivo suolisto-olosuhteita. Tutkittavat kokeelliset olosuhteet olivat käytettävän annoksen ja väliaineen vaikutukset. Tutkimukset suoritettiin neljällä eri liukoisuutta parantavalla formulaatiosuspensiolla. Tavoitteena oli selvittää tuottaako käytetty pienen mittakaavan malli saman järjestyksen formulaatiosuspensioiden välillä kuin aiemmissa rotilla suoritetuissa mittauksissa oltiin havaittu. Lisäksi tutkittiin in vitro ja in vivo -tulosten välistä korrelaatiota. Tuloksista nähtiin eroja kokeellisten olosuhteiden välillä. Erityisesti käytetyn väliaineen huomattiin aiheuttavan muuntelua tulosten välillä. Tuloksista havaittiin, että annoksella ei ollut yksinään suurta vaikutusta, mutta käytetty väliaine lisäsi myös annoksen vaikutusta. Voitiin todeta, että fosfaattipuskuri pH 3.0 väliaineessa tehdyt mittaukset tuottivat tasaisempia ja täsmällisempiä tuloksia jopa alemmalla annoksella. Sen sijaan FeSSIF väliaineessa korkeampi annos oli suositeltavampi. Tulosten perusteella FeSSIF väliaineen koostumusta ja siten sen vaikutusta dissoluutio-permeaatiomalliin tulisi tutkia vielä lisää. Neljän eri suspensioformulaatioiden välillä saatiin sama järjestys molemmilla väliaineilla ja annosmäärillä. Nämä olivat samat kuin aiemmissa in vivo -testeissä havaitut järjestykset. Tutkimuksissa saatiin myös suhteellisen korkeita korrelaatioita in vitro ja in vivo -tulosten välillä. Täten tutkittu dissoluutio-permeaatiomalli soveltuu mallintamaan rotan suolisto-olosuhteita ja sitä voidaan tulevaisuudessa käyttää tämän lääkeaineen pienen mittakaavan dissoluutio-permeaatiotutkimuksissa. Most of the newly-developed drugs are poorly-soluble and the amount of drug substance available for drug development is very limited. Therefore, there is a need to find new solubility-enhancing formulations and small-scale methods and models to study them. Drug development has utilized animal models to study drug substances’ in vivo behavior, by ranking the formulations according to the dissolved drug substance amounts with in vivo conditions. These rankings can be compared to in vitro results, which are obtained from small-scale dissolution-permeation model’s measurements. The aim of this study was to investigate what effect experimental conditions have on a small-scale dissolution-permeation model in drug development and if the studied in vitro model could efficiently simulate rat’s gastrointestinal in vivo conditions. Studied experimental conditions were dose effect and used medium’s effect. Experiments were performed with four different solubility enhancing suspension formulations. The aim was to find if used small-scale model was able to produce same ranking between suspension formulations as was previously obtained with rat studies. It was also investigated if correlation could be obtained between in vitro and in vivo results. The results indicated differences between experimental conditions. Especially used medium caused variation between results. From the results was seen that dose itself did not have a major effect, but used medium also enhanced dose’s impact. Results showed that measurements made with phosphate buffer pH 3.0 were able to produce constant and accurate results even with lower dose. With FeSSIF, higher dose was preferable, and the medium composition and thus its performance in dissolution-permeation studies needs more research. The same ranking between four suspension formulations were obtained with both media and both doses. Rankings were same as in vivo tests have been obtained. In the studies were also obtained relatively high correlations between in vitro and in vivo results. Due to correct suspension formulation rankings and good correlation between in vitro and in vivo results, it could be concluded that studied dissolution-permeation model could simulate rat’s gastrointestinal conditions. Therefore it could be used in the future, with this drug substance, for small-scale dissolution-permeation studies.
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Sen vuoksi on tarve l\u00f6yt\u00e4\u00e4 uusia liukoisuutta parantavia formulaatioita ja pienen mittakaavan metodeja ja malleja niiden tutkimiseen. L\u00e4\u00e4kekehitys on hy\u00f6dynt\u00e4nyt el\u00e4inkokeita l\u00e4\u00e4keaineiden in vivo -k\u00e4ytt\u00e4ytymisen tutkimiseen j\u00e4rjestelem\u00e4ll\u00e4 eri formulaatioita paremmuusj\u00e4rjestykseen perustuen niiden in vivo -olosuhteissa liuottamaan l\u00e4\u00e4keaineen m\u00e4\u00e4r\u00e4\u00e4n. N\u00e4it\u00e4 j\u00e4rjestyksi\u00e4 voidaan verrata in vitro -tuloksiin, jotka saadaan pienen mittakavaan dissoluutio-permeaatiomallin mittauksista.\n\nTutkimuksen tavoitteena oli tutkia kokeellisten olosuhteiden vaikutusta pienen mittakavaan dissoluutio-permeaatiomallin toimivuuteen l\u00e4\u00e4kekehityksess\u00e4. Lis\u00e4ksi haluttiin tutkia kykeneek\u00f6 tutkittava in vitro -malli tehokkaasti mallintamaan rotan in vivo suolisto-olosuhteita. Tutkittavat kokeelliset olosuhteet olivat k\u00e4ytett\u00e4v\u00e4n annoksen ja v\u00e4liaineen vaikutukset. Tutkimukset suoritettiin nelj\u00e4ll\u00e4 eri liukoisuutta parantavalla formulaatiosuspensiolla. Tavoitteena oli selvitt\u00e4\u00e4 tuottaako k\u00e4ytetty pienen mittakaavan malli saman j\u00e4rjestyksen formulaatiosuspensioiden v\u00e4lill\u00e4 kuin aiemmissa rotilla suoritetuissa mittauksissa oltiin havaittu. Lis\u00e4ksi tutkittiin in vitro ja in vivo -tulosten v\u00e4list\u00e4 korrelaatiota.\n\nTuloksista n\u00e4htiin eroja kokeellisten olosuhteiden v\u00e4lill\u00e4. Erityisesti k\u00e4ytetyn v\u00e4liaineen huomattiin aiheuttavan muuntelua tulosten v\u00e4lill\u00e4. Tuloksista havaittiin, ett\u00e4 annoksella ei ollut yksin\u00e4\u00e4n suurta vaikutusta, mutta k\u00e4ytetty v\u00e4liaine lis\u00e4si my\u00f6s annoksen vaikutusta. 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spellingShingle Hiidenhovi, Sara The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development dissolution-permeation MicroFLUX small-scale poorly-soluble drug development in vivo in vitro gastrointestinal tract biorelevant biorelevant media bioequivalance permeability flux dissolution solubility permeation biopharmaceutical biopharmaceutical classification suspension formulations Analyyttinen kemia Analytical Chemistry 40311 farmakokinetiikka imeytyminen lääketeollisuus pharmacokinetics absorption pharmaceutical industry
title The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
title_full The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
title_fullStr The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
title_full_unstemmed The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
title_short The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
title_sort effect of experimental conditions on the performance of a small scale dissolution permeation model in drug development
title_txtP The effect of experimental conditions on the performance of a small-scale dissolution-permeation model in drug development
topic dissolution-permeation MicroFLUX small-scale poorly-soluble drug development in vivo in vitro gastrointestinal tract biorelevant biorelevant media bioequivalance permeability flux dissolution solubility permeation biopharmaceutical biopharmaceutical classification suspension formulations Analyyttinen kemia Analytical Chemistry 40311 farmakokinetiikka imeytyminen lääketeollisuus pharmacokinetics absorption pharmaceutical industry
topic_facet 40311 Analytical Chemistry Analyyttinen kemia MicroFLUX absorption bioequivalance biopharmaceutical biopharmaceutical classification biorelevant biorelevant media dissolution dissolution-permeation drug development farmakokinetiikka flux gastrointestinal tract imeytyminen in vitro in vivo lääketeollisuus permeability permeation pharmaceutical industry pharmacokinetics poorly-soluble small-scale solubility suspension formulations
url https://jyx.jyu.fi/handle/123456789/82040 http://www.urn.fi/URN:NBN:fi:jyu-202206273644
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