Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus-Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.

• Klíčová slova
• Golem, biorelevant, caffeine, dissolution, multivariate data analysis,
• MeSH
• biologické modely * MeSH
• design vybavení MeSH
• farmaceutická chemie * MeSH
• farmakokinetika * MeSH
• gastrointestinální absorpce MeSH
• gastrointestinální trakt metabolismus   MeSH
• multivariační analýza MeSH
• počítačová simulace MeSH
• rozpustnost * MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• HPMC, Neusilin® US2, USP apparatus 2 dissolution test, dynamic dissolution study, matrix tablets, microcrystalline cellulose,
• Publikační typ
• časopisecké články MeSH

The rising demands on discriminatory and prediction abilities of dissolution methods and the increasing complexity of new drug products are the main driving forces of the progress in this field. The research moves forward as imperfections and shortcomings of classical methods are being described, and where the capabilities of the contemporary methods are insufficient, new methods are being developed. The review discusses these advances with respect to the issues that currently draw the most attention, i.e. correct simulation of hydrodynamics and stress forces, maintenance of sink conditions, study of precipitation, use of biorelevant media and the employment of more physiologically relevant methods in general.

• Klíčová slova
• Apparatus, biorelevant, dissolution, precipitation, sink conditions,
• MeSH
• farmaceutická chemie přístrojové vybavení   metody   MeSH
• hydrodynamika MeSH
• léčivé přípravky chemie   MeSH
• lidé MeSH
• racionální návrh léčiv * MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• léčivé přípravky MeSH

Development of new pharmaceutical compounds and dosage forms often requires in vitro dissolution testing with the closest similarity to the human gastrointestinal (GI) tract. To create such conditions, one needs a suitable dissolution apparatus and the appropriate data on the human GI physiology. This review discusses technological approaches applicable in biorelevant dissolutions as well as the physiology of stomach and small intestine in both fasted and fed state, that is, volumes of contents, transit times for water/food and various solid oral dosage forms, pH, osmolality, surface tension, buffer capacity, and concentrations of bile salts, phospholipids, enzymes, and Ca(2+) ions. The information is aimed to provide clear suggestions on how these conditions should be set in a dynamic biorelevant dissolution test.

• Klíčová slova
• bioavailability, bioequivalence, biorelevant dissolution, dissolution, dynamic dissolution, gastrointestinal physiology, gastrointestinal transit, in vitro models,
• MeSH
• farmaceutická chemie metody   MeSH
• farmakokinetika * MeSH
• gastrointestinální trakt fyziologie   MeSH
• léčivé přípravky chemie   MeSH
• lidé MeSH
• rozpustnost MeSH
• tenké střevo fyziologie   MeSH
• žaludek fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• léčivé přípravky MeSH

Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.

• Klíčová slova
• Ball milling, Co-grinding, Co-milling, Dissolution rate enhancement, In silico modelling, Multiple linear regression, Partial least squares regression,
• MeSH
• léčivé přípravky chemie   MeSH
• metoda nejmenších čtverců MeSH
• počítačová simulace MeSH
• povidon chemie   MeSH
• příprava léků * metody   MeSH
• rozpustnost * MeSH
• uvolňování léčiv * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• léčivé přípravky MeSH
• povidon MeSH

Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. Further evaluation of results was performed using IVIVC/IVIVR development. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data.

• MeSH
• atorvastatin chemie   terapeutické užití   MeSH
• farmaceutická chemie MeSH
• gastrointestinální trakt účinky léků   fyziologie   MeSH
• lidé MeSH
• tenké střevo účinky léků   MeSH
• uvolňování léčiv * MeSH
• zdravotnické prostředky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• atorvastatin MeSH

The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).

• Klíčová slova
• Bioequivalence study, Biorelevant dissolution, Meloxicam, Omeprazole, Supergeneric product,
• MeSH
• antiflogistika nesteroidní * aplikace a dávkování   chemie   farmakokinetika   MeSH
• citráty chemie   MeSH
• farmaceutická chemie MeSH
• fixní kombinace léků MeSH
• klinické křížové studie MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• meloxikam MeSH
• omeprazol * aplikace a dávkování   chemie   farmakokinetika   MeSH
• pomocné látky chemie   MeSH
• prášky, zásypy, pudry MeSH
• protivředové látky * aplikace a dávkování   chemie   farmakokinetika   MeSH
• terapeutická ekvivalence MeSH
• thiaziny * aplikace a dávkování   chemie   farmakokinetika   MeSH
• thiazoly * aplikace a dávkování   chemie   farmakokinetika   MeSH
• tobolky MeSH
• uvolňování léčiv MeSH
• želatina chemie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• Názvy látek
• antiflogistika nesteroidní * MeSH
• citráty MeSH
• fixní kombinace léků MeSH
• meloxikam MeSH
• omeprazol * MeSH
• pomocné látky MeSH
• prášky, zásypy, pudry MeSH
• protivředové látky * MeSH
• thiaziny * MeSH
• thiazoly * MeSH
• tobolky MeSH
• trisodium citrate MeSH Prohlížeč
• želatina MeSH

Current in vitro drug-release testing of the sustained-release parenterals represents the in vivo situation insufficiently. In this work, a thin agarose hydrogel layer surrounding the tested dosage form was proposed to mimic the tissue. The method was applied on implantable formulations of different geometries (films, microspheres, and cylindrical implants); prepared from various polymers (several Resomer® grades or ethyl cellulose) and loaded with different model drugs: flurbiprofen, lidocaine or risperidone. The hydrogel layer did not possess any retarding effect on the released drug and acted as a physical restriction to swelling and/or plastic deformation of the tested dosage forms. This led to a different surface area available for drug-release compared with testing in release medium alone and correspondingly to significantly different release profiles of the majority of the formulations obtained between the two methods (e.g. t50% = 18 days in pure release medium vs. t50% = 26 days in gel-setup for risperidone loaded Resomer® 503 H films or t50% = 7 days vs. t50% = 19 days for risperidone loaded Resomer® 503 H microspheres). The limited space for swelling and the rigidity of the agarose gel might mimic the tight encapsulation of the dosage form in the tissue better than the conventional liquid medium.

• Klíčová slova
• Agarose, Biorelevant, Drug release, Hydrogel, Implants, In-vitro, PLGA,
• MeSH
• kopolymer kyseliny glykolové a mléčné MeSH
• kyselina mléčná * MeSH
• kyselina polyglykolová * MeSH
• mikrosféry MeSH
• sefarosa MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kopolymer kyseliny glykolové a mléčné MeSH
• kyselina mléčná * MeSH
• kyselina polyglykolová * MeSH
• sefarosa MeSH

Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.

• Klíčová slova
• PLGA, biorelevant,, depot microspheres,, in vitro release,, intramuscular,,
• MeSH
• celulosa analogy a deriváty   MeSH
• flurbiprofen aplikace a dávkování   MeSH
• kopolymer kyseliny glykolové a mléčné MeSH
• léky s prodlouženým účinkem * MeSH
• lidokain aplikace a dávkování   MeSH
• mikrosféry MeSH
• nosiče léků MeSH
• parenterální infuze * MeSH
• pomocné látky MeSH
• prasata MeSH
• příprava léků MeSH
• risperidon aplikace a dávkování   MeSH
• svaly metabolismus   MeSH
• techniky in vitro MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• celulosa MeSH
• ethyl cellulose MeSH Prohlížeč
• flurbiprofen MeSH
• kopolymer kyseliny glykolové a mléčné MeSH
• léky s prodlouženým účinkem * MeSH
• lidokain MeSH
• nosiče léků MeSH
• pomocné látky MeSH
• risperidon MeSH

Abiraterone acetate is a potent drug used for the treatment of metastatic castration resistant prostate cancer. However, currently marketed product containing crystalline abiraterone acetate exhibits strong positive food effect which results in strict dosing regimen. In the present work, a rational approach towards design of novel abiraterone acetate formulations that would allow increased bioavailability on a fasting stomach and thus decreased food effect is presented. Precipitation experiments in biorelevant media were designed to assess pH induced precipitation of the drug and a pool of polymeric excipients was then screened for their potential to inhibit precipitation. The best performing polymeric excipients were subsequently used as carriers for the preparation of amorphous solid dispersions. Two main approaches were followed in order to formulate the drug. The first approach relies on the suppression of precipitation from a supersaturated solution whereas the second one is based on the hypothesis that when the release of the drug is tuned, optimal uptake of the drug can be reached. Optimized formulation prototypes were tested in a rat animal model in an incomplete block, randomized bioequivalence study to assess their relative bioavailability under fasting conditions. We show that both formulation approaches lead to increased bioavailability of abiraterone acetate on a fasting stomach with bioavailability in rats being enhanced up to 250% compared to the original drug product containing crystalline drug.

• Klíčová slova
• Abiraterone acetate, Bioavailability, Food effect, Precipitation, Solid dispersion, Spray drying,
• MeSH
• abirateron chemie   metabolismus   MeSH
• biologická dostupnost MeSH
• interakce mezi potravou a léky fyziologie   MeSH
• koncentrace vodíkových iontů MeSH
• krysa rodu Rattus MeSH
• omezení příjmu potravy metabolismus   MeSH
• polymery chemie   MeSH
• pomocné látky chemie   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• terapeutická ekvivalence MeSH
• uvolňování léčiv fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• abirateron MeSH
• polymery MeSH
• pomocné látky MeSH