Razvoj granulatov za polnjenje v slamico

Simšič, Tilen (author), Planinšek, Odon (mentor)

Farmacevtski trg se že kar nekaj časa srečuje s pomanjkanjem inovativnih zdravil namenjenih predvsem mlajši populaciji, ki so pogosto tudi najzahtevnejši pacienti, zato je za zadovoljivo adherenco ključna privlačna in uporabna farmacevtska oblika. V magistrski nalogi smo razvijali granulate, ki so potencialno zanimivi za nadaljnji razvoj in jih lahko apliciramo v obliki slamice z zaužito tekočino. Granule smo polnili v patentirano slamico z dvema ventiloma, ki onemogočata povratni tok tekočine. Najprej smo v slamico polnili različne pomožne snovi kot so: laktoza, sladkor, manitol, izomalt itd., in opazovali njihovo obnašanje med vlekom tekočine (potencialna zamašitev – nastanek čepov), določili pa smo jim tudi okviren čas raztapljanja. Na osnovi pomožnih snovi z ustreznim obnašanjem v slamici smo s postopkom vlažnega granuliranja v hitro-vrtečem mešalniku izdelali granule v različnih velikostnih razredih delcev, ter spremljali njihov vpliv na pretok tekočine (pojav čepov in volumen izpiranja). Granule smo ovrednotili tudi kvantitativno z na novo razvitim instrumentom, ki med vlekom tekočine meri podtlak, mogoče pa je tudi natančno določanje volumna izpiranja. Na podlagi obnašanja placebo granul v slamici, smo izdelali še granule s 30% dodatkom cefprozila, kot zdravilne učinkovine in jih ovrednotili. Med eksperimentalnim delom, smo ugotovili, da ima velikost delcev v slamici med vlekom tekočine največji vpliv na obnašanje, kjer delci večji od 710 µm znatno znižajo verjetnost za zamašitev slamice. Ugotovili smo, da so bile najboljše granule za polnjenje v slamico narejene na osnovi mletega sladkorja, kjer smo sladkor granulirali le s prečiščeno vodo, primerna pa je bila tudi granulirna tekočina na osnovi PVP K30 in SDS-a. Dodatek SDS-a v obliki granulirne tekočine med granuliranjem je močno znižal volumen izpiranja granul, po drugi strani pa so se med srkanjem podtlaki nekoliko povečali. Poleg tega smo ugotovili, da so granule z višjo vsebnostjo citronske kisline (15%) nekoliko slabše od granul z manj dodane citronske kisline (5%), za granuliranje pa je bolje uporabiti čim manjše delce. Šumeča oblika granul prav tako ni primerna za uporabo v tovrstni slamici, saj se je slamica še pred pričetkom testa popolnoma zamašila. Ugotovili smo, da ima poleg sestave pomembno vlogo tudi morfologija delcev, kjer se je pokazalo, da večji delež dodane tekočine med granuliranjem rezultira v nastanku delcev, ki imajo v slamici boljše lastnosti. Na obnašanje granul v slamici pa ima bistven vpliv tudi volumska napolnjenost slamice.

• Language: Slovenian
• Keywords: slamica, vlažno granuliranje, velikost delcev, zamašitev, SDS
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-108557
• Publication date in RUL: 06.07.2019

Secondary language

• Language: English
• Title: Development of granules for straw filling

Abstract

For some time, the pharmaceutical market has been encountering a lack of innovative drugs designed especially for the pediatric population, often the most demanding patients. Therefore, a satisfactory adherence is of key importance. In the master's thesis, granules that are potentially interesting for further development were developed. Their application is carried out by means of a drinking straw. The granules were filled into a patented straw with two valves preventing reverse water flow. First, various pharmaceutical excipients, such as lactose, sugar, mannitol, isomalt, etc., were filled in the straw, where their behavior was observed during the sipping (potential clogging - formation of plugs), and approximate dissolution time was also determined. Excipients with the best straw behavior were then granulated using a high shear mixer by wet granulation technique. Thus, granules of different particle size distributions were obtained, and their straw behavior was observed (the potential straw clogging and flush volume values of granules). Granules were also evaluated quantitatively using a newly developed instrument capable of measuring the pressure during the straw sipping and enabling a more accurate observation of the required flush volumes of granules. Based on placebo granule straw behavior, granules with 30% of cefprozil content, as a pharmaceutically active ingredient, were also manufactured. During the experimental work, it was found that the particle size in the straw has the greatest influence on straw behavior, where the particles larger than 710 ?m significantly reduce the chance of straw clogging. It was also found that the best granules for straw filling were sugar based, namely those in which milled sugar was granulated with purified water as a granulating liquid only, granulating water dispersion of PVP K30 and SDS was also good. SDS added in the form of a granulating liquid during granulation can significantly reduce granule flush volumes, but on the other hand, slightly higher sipping pressures were measured. In addition, it was found that granules with a higher citric acid content (15%) had poorer straw behavior compared to those with a lower (5%) citric acid content, and smaller citric acid particles used were more efficient. The effervescent granule is also not suitable for use in this kind of straw, as the straw was completely clogged. It was found that besides the granule composition, particle morphology plays an important role, as the higher amount of granulating liquid added during granulation results in granules having better straw properties. Straw volume filling had also a significant effect on the granule straw behavior.

• Keywords: drinking straw, wet granulation, particle size, clogging, SDS