Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10-30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices' evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10-20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.
- Publikační typ
- časopisecké články MeSH
Mikročástice jsou široce používány v nesčetných oblastech průmyslu, jako jsou farmaceutika, potraviny, kosmetika a další. Ve srovnání s tradičními metodami pro syntézu mikročástic poskytují mikrofluidní techniky výkonné platformy pro vytváření vysoce kontrolovatelných kapek emulze jako šablon pro výrobu uniformních mikročástic s pokročilými strukturami a funkcemi. Mikrofluidní techniky mohou generovat kapky emulze s přesně řízenou velikostí, tvarem a složením. Přesnější proces přípravy je účinným nástroj ke kontrole profilu uvolňování léčiva a přináší také snadno dostupnou reprodukovatelnost. Článek poskytuje informace o základních nastaveních droplet-based techniky a příklady typů mikročástic připravitelných touto metodou.
Microparticles are widely used in myriad fields such as pharmaceuticals, foods, cosmetics, and other industrial fields. Compared with traditional methods for synthesizing microparticles, microfluidic techniques provide very powerful platforms for creating highly controllable emulsion droplets as templates for fabricating uniform microparticles with advanced structures and functions. Microfluidic techniques can generate emulsion droplets with precisely controlled size, shape, and composition. A more precise preparation process brings an effective tool to control the release profile of the drug and introduces an easily accessible reproducibility. The paper gives information about basic droplet-based set-ups and examples of attainable microparticle types preparable by this method.
- Klíčová slova
- metoda odpaření rozpouštědla, mikrokanálky,
- MeSH
- mikrofluidika metody MeSH
- nanočástice * MeSH
- Publikační typ
- práce podpořená grantem MeSH
The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).
- MeSH
- deriváty hypromelózy * chemie farmakokinetika farmakologie MeSH
- kyseliny polymethakrylové * chemie farmakokinetika farmakologie MeSH
- laktosa analogy a deriváty chemie farmakokinetika farmakologie MeSH
- léky s prodlouženým účinkem farmakokinetika farmakologie MeSH
- methylcelulosa analogy a deriváty chemie farmakokinetika farmakologie MeSH
- nonoxynol * chemie farmakokinetika farmakologie MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
Přehledový článek se zaměřuje na charakterizaci (meth) akrylátových kopolymerů – Eudragitů®, popis jejich chování při tepelném ošetření, možné interakce mezi kationtovými a aniontovými polymery, inkompatibility související s Eudragity® a na jejich využití v oblasti farmaceutické technologie perorálních tablet. V přehledu jsou rozděleny na rozpustné, nerozpustné a kombinaci těchto dvou typů. Právě kombinací rozpustného a nerozpustného poly(meth)akrylátu byl získán nový typ polymeru, Eudragit® FL. V technologii perorálních tablet se Eudragity® hojně využívají v matricových tabletách, a to samostatně nebo i v kombinacích, kde zajišťují zejména prodloužené uvolňování léčiva. V menší míře se využívají v gastroretentivních systémech. Naopak velký význam mají Eudragity® v technologii potahovaných tablet, kde tyto enterosolventní polymery zajišťují specifické směřování léčiva do určitých částí trávicího traktu, zejména do tenkého střeva nebo kolonu. Jsou zde zmíněny důležité systémy jako CODESTM a MMX® technologie. V neposlední řadě je uvedena přehledová tabulka zahrnující aktuálně dostupné perorální léčivé přípravky na českém trhu, u kterých byl jako filmotvorná látka využit některý z Eudragitů®.
This review focuses on the characterization of (meth)acrylate copolymers – Eudragit®, describing their thermal treatment behaviour, possible interactions between cationic and anionic polymers, incompatibilities related to Eudragits® and their use in the pharmaceutical technology of oral tablets. In summary, Eudragit® copolymers are divided into soluble ones, insoluble ones and a combination of these two types. The combination of soluble and insoluble poly(meth)acrylate gave a new type of polymer, Eudragit® FL. In oral tablet technology, Eudragits® are widely used in matrix tablets, either alone or in combination, where they mainly provide sustained drug release. To a lesser extent, Eudragits® are used in gastroretentive systems. Moreover, Eudragits® are also of great importance in coated tablets technology, where these enteric polymers provide specific drug targeting to certain parts of the digestive tract, mainly to the small intestine or colon. Important systems such as CODESTM and MMX® technology are mentioned. Last but not least an overview table of currently available oral medicinal products on the Czech market, where at least one of the Eudragits® was used as a film-forming agent, is included.
- Klíčová slova
- Eudragit, matricové tablety, flotující tablety, acidorezistentní tablety, burst efekt, přívod léčiva do kolonu,
- MeSH
- enterosolventní tablety MeSH
- farmaceutická technologie MeSH
- kyseliny polymethakrylové MeSH
- léky s prodlouženým účinkem * MeSH
- methylmetakryláty MeSH
- nosiče léků * MeSH
- Publikační typ
- práce podpořená grantem MeSH
Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits® as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/Eudragit®NE matrices using magnesium aluminometasilicate (Neusilin® US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin® allowed the application of Eudragit® dispersion to API/Neusilin® mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit® NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150-500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit®NE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.
- MeSH
- aplikace orální MeSH
- gely MeSH
- kyseliny polymethakrylové aplikace a dávkování chemie metabolismus MeSH
- léky s prodlouženým účinkem aplikace a dávkování chemie metabolismus MeSH
- magnetická rezonanční spektroskopie metody MeSH
- pomocné látky chemie MeSH
- rozpustnost MeSH
- silikáty aplikace a dávkování chemie metabolismus MeSH
- sloučeniny hliníku aplikace a dávkování chemie metabolismus MeSH
- sloučeniny hořčíku aplikace a dávkování chemie metabolismus MeSH
- uvolňování léčiv MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
