Optimizacija izdelave pelet z lansoprazolom s termoplastičnim peletiranjem v hitrem mešalniku : doktorska disertacija

Krošelj, Vesna (author), Vrečer, Franc (mentor)

Termoplastično peletiranje v hitrem mešalniku sodi med tehnologije s talinami, ki pomenijo alternativo klasičnim (vlažnim) farmacevtskim tehnološkim postopkom in imajo pred njimi vrsto prednosti. Med temi so najpomembnejše preprostost, hitrost in ekonomičnost postopka ter primernost za vgrajevanje zdravilnih učinkovin, občutljivih na vlago. Kemijsko in fizikalno različna skupina veziv, primernih za tehnologije s talinami, omogoča fleksibilnost pri načrtovanju farmacevtskih oblik, ki jih z omenjenimi postopki lahko izdelamo. V sklopu pričujočega dela smo raziskovali primernost termoplastičnega peletiranja za izdelavo ogrodnih pelet s takojšnjim sproščanjem slabo topne zdravilne učinkovine – lansoprazola. Za to smo uporabili po dve vezivi iz skupine makrogol gliceridov (Gelucire® 44/14 in Gelucire® 50/13) in poloksamerov (Lutrol® F68 in Lutrol® F127), ki se med seboj razlikujejo v termičnih in reoloških lastnostih. V primeru makrogol gliceridov in Lutrola® F68 nam je uspelo izdelati okrogle in gladke pelete, medtem ko so bili aglomerati, izdelan iz Lutrolom® F127, nepravilne oblike in s hrapavo površino. V nasprotju z referenčnimi peletami, ki smo jih izdelali s klasičnim postopkom vlažnega peletiranja, je bilo sproščanje lansoprazola iz pelet, izdelanih s termoplastičnim peletiranjem, hitro in popolno, poleg tega pa neodvisno od analizirane velikostne frakcije pelet. Nadaljnje analize so pokazale, da je vzrok za izboljšano sproščanje enakomerna porazdelitev delcev lansoprazola v ogrodju, ki v stiku z medijem hitro razpade, hkrati pa izboljša močljivost zdravilne učinkovine. Študij vpliva procesnih in formulacijskih spremenljivk na izkoristek procesa, velikost izdelanih pelet in količino neželenih produktov (velikih aglomeratov in preostalih prahov) je pokazal, da ima v primeru veziva nizke viskoznosti (Gelucire® 50/13) največji vpliv na proces koncentracija veziva. To je posledica mehanizmov rasti, prevladujejo namreč distribucija v fazi jedrenja in enakomerna rast aglomeratov v fazi konsolidacije in koalescence. V primeru Lutrola® F68 se je pokazalo, da je bila viskoznost veziva previsoka, vseeno pa smo lahko identificirali čas gnetenja kot spremenljivko z največjim vplivom. V fazi jedrenja sta bila prisotna oba mehanizma, tako distribucija kot imerzija, rast aglomeratov pa je bila prav tako kombinacija enakomerne rasti in indukcije. Granulacijski grafi, ki kažejo navor mešala v odvisnosti od časa, so se pokazali kot primerno orodje za spremljanje procesa, predvsem v smislu zaznavanja destruktivne faze. Medtem ko v primeru Lutrola® F68 velikost pelet ni korelirala z navorom, smo v primeru Gulucire® 50/13 opazili linearno odvisnost doseženega navora in povprečne velikosti izdelanih pelet. Box-Behnkenov eksperimentalni načrt in metoda odgovornih površin sta poleg določitve vpliva posameznih parametrov omogočila tudi optimizacijo procesa. Napovedane vrednosti odzivov, ki smo jih dobili z matematičnim (regresijskim) modelom, smo potrdili in modela uspešno validirali, ne glede na uporabljeno vezivo. Rezultati naloge kažejo, da je termoplastično peletiranje v hitrem mešalniku dobra alternativa klasičnim tehnološkim postopkom, uporaba hidrofilnih veziv pa omogoča izdelavo pelet s takojšnjim sproščanjem slabo topne učinkovine. Občutljivost postopka na spremembe procesnih spremenljivk je mogoče obvladovati z identifikacijo, optimizacijo in natančnim nadzorom ključnih parametrov.

• Language: Slovenian
• Keywords: pelete, izdelava pelet, karakterizacija pelet, analiza, vrednotenje pelet
• Work type: Dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [V. Krošelj]
• Year: 2008
• Number of pages: 166 f.
• PID: 20.500.12556/RUL-127018
• UDC: 542:661.12
• COBISS.SI-ID: 2261617
• Publication date in RUL: 13.05.2021

Secondary language

• Language: English
• Title: Optimization of the production of lansoprazole pellets by thermoplastic pelletization in a high shear mixer

Abstract

Thermoplastic pelletization in a high-shear mixer is one of the hot-melt technologies, which represent a viable alternative to classical pharmaceutical technological processes and offer a number of advantages. Among these are simplicity, shorter processing times and cost effectiveness as well as the suitability for incorporation of moisture-sensitive active ingredients. A chemically and physically versatile group of melting binders assures flexibility in the design of the pharmaceutical dosage forms, which can be produced using the above-mentioned processes. The aim of this study was to evaluate the thermoplastic pelletization process as a method for the production of immediate-release matrix pellets containing a poorly soluble model drug – lansoprazole. Two types of binders were used for the preparation of the pellets, macrogolglycerides (Gelucire® 44/14, Gelucire® 50/13) and poloxamers (Lutrol® F68 and Lutrol® F127), which differ in rheologic and thermal behaviour. In the case of macrogolglycerides and Lutrol® F68, the produced pellets were round and smooth whereas the agglomerates containing Lutrol® F127 were of irregular shape and rugged surface. Compared to the reference pellets, produced by wet pelletization, the release of the drug from the pellets produced by thermoplastic pelletization was fast and complete, irrespective of the fraction analyzed. Further studies suggested that the improvement in dissolution rate can be explained by the fine distribution of lansoprazole in the matrix which quickly disintegrates in contact with media and improves wettability of the drug. The study of the influence of process and formulation parameters on the process yield, pellet size and amount of unwanted by-products (lumps and remaining undersized particles) showed that the concentration of binder in the pellet mixture has the highest influence on the process in the case of a low-viscosity binder (Gelucire® 50/13). This is the result of growth mechanisms, with distribution being predominant in the nucleation phase and steady growth in the consolidation phase. Although the viscosity of the binder was shown to be too high to achieve a controllable process in the case of Lutrol® F68, massing time was still identified as the variable that most influenced the pelletization process. Both distribution and immersion mechanisms were present in the nucleation phase. The consolidation phase was also a combination of induction and steady growth. Granulation graphs, which show changes of torque over time, proved an appropriate tool for process supervision, particularly in detecting the destructive phase. While in the case of Lutrol® F68 pellet size did not correlate with torque, we observed a linear relationship between torque and mean pellet size in the case of Gelucire® 50/13. The Box-Behnken experimental design and the response surface methodology allowed both for the determination of the influence of particular process parameters and for their optimization. The predicted response values obtained mathematically (by regression model) were confirmed experimentally and the models were successfully validated, regardless of the binder used. The results of the present work show that thermoplastic pelletization in a high-shear mixer is a simple and effective alternative to classical pharmaceutical methods and that the use of hydrophilic melting binders allows the production of immediate-release pellets containing a poorly soluble drug. The sensitivity of the process to the changes in process parameters can be overcome by their identification, optimization and careful control.