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®, acidoresistant tablets, burst effect, colon drug delivery, film-coating tablets, floating tablets, matrix tablets, prolonged drug release,
• MeSH
• farmaceutická chemie * MeSH
• kyseliny polymethakrylové chemie   MeSH
• léky s prodlouženým účinkem MeSH
• rozpustnost MeSH
• tablety * MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• kyseliny polymethakrylové MeSH
• léky s prodlouženým účinkem MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• tablety * MeSH

BACKGROUND/AIMS: Administration of tablets via feeding tube (FT) is often associated with significant drug losses, as was confirmed by weighing. The aim of this study was to measure the proportion of active substance losses (ASLs) in an in vitro model. METHODS: A film-coated tablet (FilmCT) containing clopidogrel (Trombex®) and a tablet with enteric coating (EntericCT) containing pantoprazole (Controloc®) were crushed in a mortar and transferred by method A (tablet powder was transferred into the beaker, poured into the syringe and water added) and method B (water was added into the mortar, suspension drawn into the syringe) and administered via FT in an in vitro model. Total losses were measured with analytical balance and, simultaneously, ASL were analyzed with high-performance liquid chromatography UV-detection (HPLC-UV). RESULTS: ASL was different to weighing only in the case of EntericCT prepared by method B (2.0 ± 4.2 and 10.7 ± 0.8% for HPLC-UV and weighing, respectively; p = 0.004). HPLC-UV confirmed significantly lower ASL when method B was used for either EntericCT (34.3 ± 7.2 vs. 2.0 ± 4.2%; p < 0.001) or FilmCT (14.1 ± 2.2 vs. 7.7 ± 4.1%; p < 0.01). CONCLUSION: Drug loss analysis with analytical balance may overestimate ASL, as was proved for EntericCT in this study. ASL were significantly lower when method B was used.

• Klíčová slova
• Dosage forms, Drug administration routes, High-pressure liquid chromatography, Intensive care, Nasogastric tube,
• MeSH
• enterální výživa přístrojové vybavení   MeSH
• enterosolventní tablety MeSH
• gastrointestinální intubace * MeSH
• klopidogrel aplikace a dávkování   chemie   MeSH
• pantoprazol aplikace a dávkování   chemie   MeSH
• spektrofotometrie ultrafialová metody   MeSH
• tablety MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Publikační typ
• srovnávací studie MeSH
• validační studie MeSH
• zprávy MeSH
• Názvy látek
• enterosolventní tablety MeSH
• klopidogrel MeSH
• pantoprazol MeSH
• tablety MeSH

We introduce atomic layer deposition (ALD) as a novel method for the ultrathin coating (nanolayering) of minitablets. The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit® E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications.

• Klíčová slova
• Atomic layer deposition, Minitablet, Polymer film coating, Taste masking, Thin film coating, TiO(2),
• MeSH
• chuť MeSH
• farmaceutická technologie metody   MeSH
• kyseliny polymethakrylové MeSH
• rozpustnost MeSH
• tablety * MeSH
• titan MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny polymethakrylové MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• tablety * MeSH
• titan MeSH
• titanium dioxide MeSH Prohlížeč

To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film-coated tablet formulation of macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0-t ), and plasma concentration-time curve from zero to infinity (AUC0-∞ ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.

• Klíčová slova
• bioavailability, clinical trials, pediatrics, respiratory medicine,
• MeSH
• biologická dostupnost MeSH
• dítě MeSH
• dospělí MeSH
• klinické křížové studie MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• omezení příjmu potravy metabolismus   MeSH
• plocha pod křivkou MeSH
• pyrimidiny aplikace a dávkování   krev   farmakokinetika   MeSH
• sulfonamidy aplikace a dávkování   krev   farmakokinetika   MeSH
• tablety MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH
• tablety MeSH

Oral mucoadhesive tablets belong to modern dosage forms, which allow controlled drug release after buccal application. They are used for the treatment of oral cavity disorders or for systemic administration of drugs with high first-pass effect or drugs instable in gastrointestinal tract. This study reports the development of oral mucoadhesive tablets containing antimycotic drug ciclopiroxolamine. Mucoadhesive properties of placebo tablets containing different ratios of carbomer and hydroxypropylmethylcellulose were evaluated in vivo in healthy human volunteers. The longest mucoadhesion for 9 hours was achieved in matrices containing 60% (w/w) of carbomer. When optimum combination of the two mucoadhesive polymers was selected, tablets containing ciclopiroxolamine were prepared and one tablet side was film-coated to make the application procedure easier. Tablet quality parameters were determined and drug dissolution profile was evaluated under different pH conditions. In vitro release of ciclopiroxolamine was slower than the desintegration of prepared mucoadhesive tablets in vivo. Nevertheless, tablets containing 25 mg of ciclopiroxolamine performed prolonged drug release with oral mucosa concentrations higher than its MIC of relevant pathogens.

• MeSH
• adhezivita MeSH
• antifungální látky aplikace a dávkování   MeSH
• aplikace bukální MeSH
• ciklopirox MeSH
• farmaceutická technologie MeSH
• hodnocení léčiv MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• pyridony aplikace a dávkování   MeSH
• tablety * MeSH
• ústní sliznice MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antifungální látky MeSH
• ciklopirox MeSH
• léky s prodlouženým účinkem MeSH
• pyridony MeSH
• tablety * MeSH

PURPOSE: Drug administration through nasogastric tube (NGT) is a standard practice but the real amount of the delivered drug is unknown. Therefore, we designed a study to determine the losses of various dosage forms administered by different methods through NGT. METHODS: In vitro model was used. Five different administration methods (A-E) and six dosage forms (simple compressed tablets - T/S; film coated tablets - T/FC; enteric coated tablets - T/EC; capsules with powder filling - C/P; capsules containing extended release pellets - C/ER; capsules containing gastro-resistant pellets - C/GR) were investigated. Measurement was repeated six times for each drug-method combination. The overall losses were determined by gravimetry. In method A partial losses associated with each step of drug administration were also determined. RESULTS: Significant drug losses were measured (4-38%). Only methods A (crushing-beaker-syringe-water-NGT) and B (crushing-water-syringe-NGT) were suitable for administration of all tested dosage forms. Method B proved the most effective for all kinds of tablets and C/GR (p<0.05) and tended to be more effective also for C/ER (p=0.052) compared to method A. C/P showed minimal losses for both tested methods (B and E). Flushing of the drug through NGT causes major losses during drug administration compared to crushing and transfer (p<0.05). All methods for intact pellets (C-E) were found inappropriate for clinical practice due to NGT clogging. CONCLUSIONS: Choosing a suitable administration method can significantly affect the amount of drugs delivered through NGT.

• Klíčová slova
• Dosage forms, Drug administration, Enteral feeding, Intensive care, Nasogastric tube,
• MeSH
• gastrointestinální intubace * MeSH
• léčivé přípravky aplikace a dávkování   chemie   MeSH
• léky s prodlouženým účinkem aplikace a dávkování   chemie   MeSH
• tablety aplikace a dávkování   chemie   MeSH
• tobolky aplikace a dávkování   chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• léčivé přípravky MeSH
• léky s prodlouženým účinkem MeSH
• tablety MeSH
• tobolky MeSH

Pellets containing rutin prepared by the extrusion/spheronization method were coated with sodium alginate-chitosan film. Important quality parameters in the pellets before coating were determined, and after coating the dissolution profiles of the drug were evaluated in dissolution media of the pH corresponding to the conditions in the gastrointestinal tract. Samples of coated pellets were located in the boxes for stability testing under different conditions, i.e. 25 degrees C and 60% of relative humidity (RH); 30 degrees C and 65% RH and 40 degrees C and 75% RH. After 1, 3, 6, 9 and 12 months (or 1, 3 and 6 months), the dissolution test was repeated and compared with the original profiles using similarity factors. All similarity factor values above 50 indicate excellent stability of alginate-chitosan films.

• MeSH
• algináty * chemie   MeSH
• chitosan * chemie   MeSH
• enterosolventní tablety * farmakokinetika   MeSH
• rozpustnost MeSH
• rutin MeSH
• techniky in vitro MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• algináty * MeSH
• chitosan * MeSH
• enterosolventní tablety * MeSH
• rutin MeSH

The possibility of N-Nitrosation in the absence of nitrosating agents was studied on model solutions and film coated tablets containing metformin. N-nitrosodimethylamine (NDMA) and N-nitrosation precursors (dimethylamine and nitrites) were determined using previously published fully validated analytical methods. Alternative routes to N-nitrosation were found. Dimethylamine can undergo an oxidation to nitrite in the presence of strong oxidants (e.g., H2O2), as was observed during wastewater treatment in several published works. The resulting nitrite can consecutively act as a nitrosating agent. We proved that the described reaction indeed leads to N-nitrosation (NDMA formation in case of dimethylamine precursor) in model solutions made of dimethylamine and H2O2. An experiment was designed in order to prove those reactions take place in dosage forms. Film coated tablets present a highly heterogenous system with several solid phases and low water activity, which is in stark contrast to the liquid wastewater, where this reaction was originally studied. Despite that, the described reaction took place even in the tablets, but only to a small degree. The amount formed via this alternative route corresponds to less than 10 % of the total formed NDMA. The pH optimum of this alternative route lies in the alkaline range which was confirmed by the determined NDMA concentration in model solutions. The solid phase system (i.e., tablets) was found to behave differently. The addition of Na2CO3 into the tablets during manufacture resulted in tablets without NDMA (cNDMA < LOQ) even in batches spiked with both dimethylamine and H2O2. Thus, adjusting the pH of the solid dosage forms remains a sufficient measure of controlling N-nitrosamines in the product, even in product with limit amounts of oxidating agent (H2O2) and N-nitrosation precursor (dimethylamine).

• Klíčová slova
• Metformin, N-nitrosodimethylamine, Nitrite, Nitrosamines, Oxidation of dimethylamine, Self-nitrosation, UPLC-MS,
• MeSH
• dimethylaminy MeSH
• dimethylnitrosamin MeSH
• dusitany * MeSH
• léčivé přípravky MeSH
• nitrosace MeSH
• peroxid vodíku * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dimethylaminy MeSH
• dimethylnitrosamin MeSH
• dusitany * MeSH
• léčivé přípravky MeSH
• peroxid vodíku * MeSH

An effective analytical method for the quantification of N-nitrosodimethylamine (NDMA) using a liquid chromatography coupled with tandem mass spectrometry was developed and applied to a process optimization study of the production of metformin film coated tablets in order to identify the key factors behind the NDMA formation in metformin products. The method uses a linear gradient elution with mobile phases 0.1 % formic acid in water for chromatography and methanol for chromatography and a column Acquity UPLC HSS T3 1.8 μm. The use of the tandem mass spectrometry in a positive ion mode with an atmospheric pressure chemical ionization allows for the use of an isotopically labelled internal standard and an external calibration standard. The method was validated according to the guidelines of International Council for Harmonization in terms of limit of detection and quantification, linearity, precision, accuracy and method selectivity. To further justify the effectiveness of the method, a comparison between two laboratories was performed using a linear regression testing. Both methods give comparable results. 469 samples of both metformin active pharmaceutical ingredient and film coated tablets were analysed and the key factors behind NDMA formation were identified. Hypotheses explaining the mechanism were formulated and confronted with measurements and scientific literature. Protective measures to prevent NDMA contamination in metformin products were drawn.

• Klíčová slova
• Metformin, N-nitrosamines, N-nitrosodimethylamine, Pharmaceutical analysis, Tandem mass spectrometry,
• MeSH
• chromatografie kapalinová MeSH
• dimethylnitrosamin * MeSH
• kontaminace léku MeSH
• metformin * MeSH
• reprodukovatelnost výsledků MeSH
• tandemová hmotnostní spektrometrie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dimethylnitrosamin * MeSH
• metformin * MeSH