Razvoj zrnc s cefuroksimom in njihovo oblaganje za prikrivanje grenkega okusa

Vidic, Tjaša (author), Planinšek, Odon (mentor)

Grenak okus učinkovin predstavlja za farmacevtsko industrijo velik izziv, posebno, kadar so zdravila namenjena peroralni aplikaciji za otroško populacijo. Prikritje grenkega okusa lahko veliko pripomore k povečanemu sodelovanju pacientov pri zdravljenju in k izboljšanju kliničnih izidov. Veliko zdravilnih učinkovin ima neprijeten okus, zato je znanih več različnih tehnik za njegovo prikrivanje. Na ravni formulacije se dodaja različna sladila in arome, v novejšem času razvijamo tudi spojine z antagonističnim delovanjem na receptorje za grenko v ustih, ali pa izkoriščamo različne fizikalno-kemijske lastnosti učinkovine, s čimer zmanjšamo njeno topnost v ustih. Na molekulski ravni uporabljamo tvorbo kompleksov z ionsko-izmenjevalnimi smolami in ciklodekstrini, ali pa izkoriščamo tvorbo medmolekulskih interakcij z biološkimi makromolekulami. Najpogosteje uporabljena metoda za prikrivanje okusa je oblaganje delcev, s čimer tvorimo fizikalno bariero, ki preprečuje neposreden stik grenkih učinkovin z receptorji za grenko. Pri delu smo razvili prototip generičnega zdravila z vsebujočo učinkovino aksetilcefuroksimat, kateremu smo ustrezno prikrili grenak okus, poleg tega pa smo proučevali tudi možnost formulacije zrnc za uporabo v slamici. Najprej smo s primerjavo različnih tehnik granuliranja ugotovili, da se zrnca, izdelana v vrtičnoslojnem granulatorju, bolje obnašajo pri vleku v slamici kot zrnca, izdelana s hitro vrtečim mešalnikom. Najustrezneje so se pri vleku po slamici izkazala zrnca, ki pripadajo velikostnemu razredu od 710 do 1120 µm. Zaradi omejitve volumna v slamici smo za granuliranje jeder izbrali hitro vrteči mešalnik. V nadaljevanju smo ugotavljali vpliv deleža stearinske kisline v formulaciji in pri tem ugotovili, da višji delež stearinske kisline povzroči boljše prikrivanje grenkega okusa in vpliva na upočasnjeno sproščanje učinkovine. Na vlek po slamici ima stearinska kislina zelo slab vpliv, kar smo želeli s sladkornim oblaganjem zrnc izboljšati. Ugotovili smo, da sladkorna obloga sicer prispeva k boljšemu vleku skozi slamico, vendar pa s sladkornim oblaganjem zrnc ne moremo povečati v tolikšni meri, da bi hidrofilen sloj omogočal popolno izpraznitev zrnc iz slamice. V nadaljevanju smo grenak okus prikrili s tvorbo fizikalne bariere, pri čemer smo uporabili Eudragit® E PO in HPMC. Pri obeh uporabljenih polimerih smo ustrezno prikrili grenak okus, vendar ugotovili, da HPMC zelo slabo vpliva na vlek po slamici zaradi nabrekanja, Eudragit® E PO pa je izkazal boljše lastnosti. S testi sproščanja smo ugotovili, da oblogi ne vplivata bistveno na sproščanje učinkovine, saj smo se z rezultati približali referenčnemu zdravilu.

• Language: Slovenian
• Keywords: prikrivanje okusa, cefuroksim, granuliranje, oblaganje, sproščanje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-108332
• Publication date in RUL: 28.06.2019

Secondary language

• Language: English
• Title: Development of granules with cefuroxime and their coating for masking bitter taste

Abstract

The bitter taste of active ingredients is a great challenge for the pharmaceutical industry, especially when drugs are intended for oral use for the paediatric population. Masking of the bitter taste can greatly contribute to increased adherence and improve clinical outcomes. A lot of active ingredients have an unpleasant taste, so several different techniques for masking bitter taste are used. At the level of the formulation various sweeteners and aromas are added, nowadays many compounds with antagonistic effect on bitter taste receptors are being developed, or various physico-chemical properties of the active ingredient are used with the aim of reducing the solubility of the active ingredient in the mouth. At the molecular level, the formation of complexes with ion-exchange resins and cyclodextrins is used or the formation of intermolecular interactions with biological macromolecules is applied. The most commonly used taste masking technique is particle coating, thus forming a physical barrier that prevents the direct contact of the bitter substances with taste receptors. In our work we developed a prototype of the generic drug containing the cefuroxime axetil as active substance with appropriately masked bitter taste. We also studied the possibility of granules formulation in the straw. By comparing different granulation techniques, it was found that the granules produced in fluid bed granulator are more suitable for formulation in the straw than granules produced by a high shear mixer. The most suitable granules for formulation in the straw were those belonging to the size class from 710 to 1120 µm. For the granulation of nucleuses we chose high shear mixer due to the limitation of the volume in the straw. The influence of the stearic acid content in the formulation was determined. It was found that a higher content of stearic acid results in a better taste masking and slows down the release of active substance. Stearic acid has a very bad influence on the straw suction, which we wanted to improve with sugar coating of the granules. We found that sugar coating contributes to a better pulling through the straw, but with sugar coating granules can not be increased to such an extent that the hydrophilic layer will allow the complete emptying of the granules from the straw. In the following, the bitter taste was masked by the formation of a physical barrier, using Eudragit® E PO and HPMC. At both polymers used we appropriately masked the bitter taste, but it was found that HPMC had a very poor effect on straw barge suction due to swelling while Eudragit® E PO showed better properties. With the drug release tests it was found that the coating layers do not affect the release of the active ingredient significantly, as the results were similar to the reference drug.

• Keywords: taste masking, cefuroxime, granulation, coating, drug release