Browsing by Subject "dissoluutio"
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(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).
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(2020)Tiivistelmä/Referat – Abstract Background: Biotin is marketed specifically for its hair and nail growth-promoting effects, and its use has become more common in recent years. High doses of 100 mg biotin have also been used to treat MS. There are no high-dose oral products on the Finnish pharmaceutical market. Biotin 100 mg tablets are not available on the global pharmaceutical market either. The University Pharmacy manufactures 100 mg biotin capsules for hospital use. Manual manufacturing of biotin capsules is a resource-intensive process. The physicotechnical properties of biotin such as crystal properties, flowability, hygroscopicity, true density and compressibility properties have not been previously published in the literature. Objectives: The aim of the thesis work was to investigate whether high-dose biotin tablets can be manufactured as an industrial-scale process. To support product development decision-making, the aim of the master's thesis was also to explore the physicotechnical properties of biotin. The main goal was to develop a method for the direct compression of biotin tablets, but also to study the applicability of the wet granulation method. Methods: The crystal form of the raw materials was examined by X-ray powder diffractometer, particle size and particle size distribution by laser velocimeter, and compression behavior by tabletability tests as well as Heckel analysis. The flowability of the raw materials was studied by bulk and tapped density measurements. The production of biotin tablets was studied with six test batches, two of which were high shear wet granulated and four were direct compression processes. The tablets were subjected to European Pharmacopoeia quality tests such as friability, disintegration, and dissolution tests. Results: The particle size distribution of the biotin grade used in the tablets was wide, with an average particle size of 58 μm. Biotin crystals are flaky in shape. Biotin used was the α-crystalline form and its crystalline form did not change as a result of high shear wet granulation. The flow of the biotin grade was extremely poor. Biotin was not found to be particularly hygroscopic. Biotin is brittle, and when compressed, it forms by fragmenting. Pure biotin cannot be compressed into a stable tablet, as even tablets made with high compression forces will form a lid from which the tablet will easily crumble. Biotin sticks to tablet machine’s punches and causes problems in the ejection phase due to high frictional forces. Test batches of the high shear wet granulation process were successful on both eccentric and rotary tablet machine. Two batches of direct compression tests performed on rotary tablet machines had to be stopped after the powder mass got stuck in tablet machine’s hopper. Biotin tablet’s dissolution was slow for all the manufactured batches, with an average of 63-73 % biotin dissolution at 45 min time point. Conclusions: Main property to be optimized for biotin tablet formulations proved to be mass flowability. High shear wet granulation improved significantly flowability. Weight variance of the tablets in the wet granulation batches was also very small. Biotin’s slow dissolution from the tablets was another significant challenge for all the test batches. Further development of biotin tablets should therefore focus on investigating, which measures accelerate biotin tablet’s dissolution. Product development would particularly benefit from the development of a more efficient, ultra-high performance liquid chromatography method for dose analysis of biotin tablets. Wet granulation test batches should be manufactured at different process parameter levels with different excipients and excipient concentrations. Design of experiments statistical approach should be utilized for these further studies so that factor interactions could be detected, and the manufacturing process and drug product could be efficiently optimized.
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(2020)Tiivistelmä/Referat – Abstract Tausta: Biotiinia markkinoidaan erityisesti sen hiuksien ja kynsien kasvua edistävien vaikutuksien perusteella, ja sen käyttö on yleistynyt viime vuosina. Suuriannoksista 100 mg:n biotiinia on käytetty myös MS-taudin hoidossa. Suomen lääkemarkkinoilla ei ole suuriannoksisia suun kautta otettavia valmisteita. 100 mg:n biotiinitabletteja ei löydy koko maailman lääkemarkkinoilta. Yliopiston Apteekki valmistaa 100 mg:n biotiinikapseleita sairaalakäyttöön. Manuaalinen biotiinikapseleiden valmistus on resursseja intensiivisesti kuluttava prosessi. Biotiinin fysikoteknisiä ominaisuuksia kuten kideominaisuuksia, valuvuutta, hygroskooppisuutta, todellista tiheyttä ja puristuvuusominaisuuksia ei ole aiemmin julkaistu kirjallisuudessa. Tavoitteet: Gradutyön tavoitteena oli kartoittaa, onko suuriannoksisia biotiinitabletteja mahdollistaa valmistaa teollisen mittakaavan prosessina. Tuotekehityksen päätöksenteon tukemiseksi gradutyön tavoitteena oli myös kartoittaa biotiinin fysikoteknisiä ominaisuuksia. Pääasiallisena tavoitteena oli kehittää biotiinitablettien suorapuristusvalmistusmenetelmä, mutta tutkia myös märkärakeistusmenetelmän soveltuvuutta. Menetelmät: Raaka-aineiden kidemuotoa tutkittiin röntgenjauhediffraktometrilla, partikkelikokoa ja partikkelikokojakaumaa laservelosimetrillä, ja puristumiskäyttäytymistä tabletoitavuuskokeilla sekä Heckel-analyysillä. Raaka-aineiden valuvuutta tutkittiin kaato- ja tärytiheysmittauksilla. Biotiinitablettien valmistusta tutkittiin kuudella tabletointikoe-erällä, joista kaksi oli high shear- märkärakeistuksella tehtyjä ja neljä suorapuristusprosesseja. Tableteille suoritettiin Euroopan farmakopean mukaisia laatutestejä kuten murenevuus-, hajoamis-, ja dissoluutiotestit. Tulokset: Tabletteihin käytetyn biotiinilaadun partikkelikokojakauma oli leveä, ja keskimääräinen partikkelikoko 58 µm. Biotiinikiteet ovat muodoltaan hiutalemaisia. Biotiini oli α-kidemuotoa, ja sen kidemuoto ei muuttunut high shear- märkärakeistuksen seurauksena. Biotiinilaadun valuvuus oli äärimmäisen huono. Biotiini ei osoittautunut erityisen hygroskooppiseksi. Biotiini on haurasta, ja puristuessaan se muotoutuu murtumalla. Puhdasta biotiinia ei saa puristettua koossa pysyväksi tabletiksi, sillä suurillakin puristusvoimilla valmistettuihin tabletteihin muodostuu kansi, josta tabletti lähtee herkästi murenemaan. Biotiini tarttuu tablettikoneen painimiin ja aiheuttaa ongelmia muotista poistettaessa suuren kitkavoiman takia. High shear- märkärakeistusprosessin tabletointikoe-erät onnistuivat sekä epäkesko- että rotaatiotablettikoneella. Kaksi rotaatiotablettikoneilla suoritettua suorapuristuskoe-erää jouduttiin keskeyttämään jauhemassan juututtua syöttöastiaan. Kaikkien koe-erien tablettien biotiinin liukeneminen oli hidasta, sillä keskimäärin 45 minuutin kohdalla tablettien biotiinista oli liuennut 63-73 %. Johtopäätökset: Biotiinitablettien formulaation tärkeimmäksi optimoitavaksi ominaisuudeksi osoittautui massan valuvuus. High shear- märkärakeistus paransi merkittävästi massan valuvuutta. Märkärakeistuskoe-erien tablettien painonvaihtelu oli hyvin pientä. Kaikkien koe-erien merkittävänä haasteena oli kuitenkin biotiinin hidas vapautuminen tableteista. Biotiinitablettien jatkokehityksen tulisikin keskittyä dissoluutiota nopeuttavien toimenpiteiden tutkimiseen. Tuotekehitys hyötyisi erityisesti uuden, tehokkaamman, ultrakorkean suorituskyvyn nestekromatografiamenetelmän kehittämisestä biotiinitablettien annosanalytiikkaan. Märkärakeistuskoe-eriä tulisi tehdä eri prosessiparametritasoissa sekä eri apuaineilla ja apuaineiden pitoisuuksilla. Koe-erien suunnittelussa tulisi hyödyntää tilastollista koesuunnittelua muuttujien välisien interaktioiden vaikutuksien havaitsemiseksi, ja tuotantoprosessin sekä lopputuotteen tehokkaan optimoinnin varmistamiseksi.
Now showing items 1-3 of 3