There is a growing interest in using deep eutectic solvents (DES) as a pharmaceutical delivery system for poorly water-soluble compounds. To reduce the risk of drug precipitation following oral administration, this study addresses the hypothesis that directly including a polymeric precipitation inhibitor (PI) in a DES mixture could obtain a polymer-embedded deep eutectic system (PEDES) as a novel bio-enabling formulation principle. Following broad formulation screening, a PEDES embedding 15% w/w of polyvinyl pyrrolidone K30 (PVP) in L-carnitine:ethylene glycol (1:4, molar ratio) DES was successfully formulated as a supersaturating formulation using indomethacin as model compound. The drug solubility of 175.6 mg/mL obtained in DES was remarkably high, and upon release (phosphate buffer, pH 6.5) a maximum supersaturation factor of 9.8 was recorded, whereby the release kinetics displayed a suitable "parachute effect". The formulation was further characterized to include a molecular dynamics simulation. It can be concluded that PEDES appears to be a viable novel formulation approach, setting solid grounds for further research to assess the full potential of this novel type of supersaturating drug delivery system.
- MeSH
- adherence k farmakoterapii MeSH
- hormony farmakologie terapeutické užití MeSH
- komplementární terapie * MeSH
- léčivé přípravky * chemie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- populární práce MeSH
A set of new mixed-mode ion-exchange stationary phases is presented. The backbone of organic selectors is formed by a linear hydrocarbon chain, which is divided into two parts of various lengths by a heteroatom (oxygen or nitrogen). In all studied cases, there is a sulfonic acid moiety as the terminal group. Therefore, selectors bearing oxygen gave rise to strong cation ion-exchange stationary phases, while selectors with an embedded nitrogen atom (inducing a weak anion exchange capacity) were used to create zwitterion ion-exchange stationary phases. The new mixed-mode stationary phases were chromatographically evaluated in high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) using isocratic elution conditions to disclose their chromatographic potential. In HPLC mode, aqueous-rich reversed phase chromatography, acetonitrile-rich hydrophilic interaction liquid chromatography and methanolic ion-exchange chromatography mobile phases were employed. In these chromatographic modes, retention factors and selectivity values for a test set of basic and zwitterionic analytes were determined. The results were compared and principal component analysis for each chromatographic mode was performed. For all chromatographic modes, the component 1 in the principal component analysis reflected the elution order. The application of different mobile phases on a particular column resulted not only in variation in retention, but also in modified selectivity, and different elution order of the analytes. The orthogonality of the elution order depending on the employed mobile phase conditions was especially reflected for structurally closely related analytes, such as melatonin and N-acetyl-serotonin, tryptamine and serotonin or noradrenalin and octopamine. However, ion-exchange interactions remain the main driving force for retention. From all investigated stationary phases, the SCX 2 (C5-linker and C4-spacer) seems to be the best choice for the separation of basic analytes using different mobile phase conditions.
- MeSH
- acetonitrily chemie MeSH
- anionty chemie MeSH
- biogenní aminy izolace a purifikace MeSH
- chemie farmaceutická metody MeSH
- chromatografie metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- iontová výměna MeSH
- kationty chemie MeSH
- léčivé přípravky chemie izolace a purifikace MeSH
- methanol chemie MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
The coupling of columns in sub/supercritical fluid chromatography presents a great opportunity for influencing the separation efficiency and extending the selectivity of the separation system. Combinations of different types of chiral stationary phases could positively affect the enantioresolution if single ones are complementary to each other. In this work, two superficially porous particle (2.7 μm) macrocyclic glycopeptide-based columns, namely TeicoShell and NicoShell, were serially coupled and tested in sub/supercritical fluid chromatography for the first time. The influence of the column arrangement on the enantioseparation of structurally diverse biologically active compounds was examined. The obtained results showed how the column order crucially affected the enantioresolution of compounds tested, but the retention was negligibly affected in most cases. We also demonstrated that single TeicoShell and NicoShell columns are very promising towards the development of highly efficient and fast/ultrafast sub/supercritical fluid chromatography methods for structurally different chiral compounds. The optimized methods for sub-minute enantioselective separation of certain biologically important compounds were proposed.
Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.
- MeSH
- aminy chemie MeSH
- antibakteriální látky chemie MeSH
- ciprofloxacin chemie MeSH
- fosfáty chemie MeSH
- koncentrace vodíkových iontů MeSH
- kyselina mléčná chemie MeSH
- léčivé přípravky chemie MeSH
- prekurzory léčiv chemie MeSH
- systémy cílené aplikace léků metody MeSH
- Publikační typ
- časopisecké články MeSH
Recently, the 1H-detected in-cell NMR spectroscopy has emerged as a unique tool allowing the characterization of interactions between nucleic acid-based targets and drug-like molecules in living human cells. Here, we assess the application potential of 1H and 19F-detected in-cell NMR spectroscopy to profile drugs/ligands targeting DNA G-quadruplexes, arguably the most studied class of anti-cancer drugs targeting nucleic acids. We show that the extension of the original in-cell NMR approach is not straightforward. The severe signal broadening and overlap of 1H in-cell NMR spectra of polymorphic G-quadruplexes and their complexes complicate their quantitative interpretation. Nevertheless, the 1H in-cell NMR can be used to identify drugs that, despite strong interaction in vitro, lose their ability to bind G-quadruplexes in the native environment. The in-cell NMR approach is adjusted to a recently developed 3,5-bis(trifluoromethyl)phenyl probe to monitor the intracellular interaction with ligands using 19F-detected in-cell NMR. The probe allows dissecting polymorphic mixture in terms of number and relative populations of individual G-quadruplex species, including ligand-bound and unbound forms in vitro and in cellulo. Despite the probe's discussed limitations, the 19F-detected in-cell NMR appears to be a promising strategy to profile G-quadruplex-ligand interactions in the complex environment of living cells.
- MeSH
- DNA chemie účinky léků MeSH
- G-kvadruplexy účinky léků MeSH
- konformace nukleové kyseliny účinky léků MeSH
- léčivé přípravky chemie MeSH
- lidé MeSH
- ligandy MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární modely MeSH
- protony MeSH
- vazebná místa účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In this report, we employed the solid-phase synthetic approach to prepare variously substituted dihydropteridinones, tetrahydropyrrolopteridinones, and pyrimidodiazepinones, using a versatile building block-4,6-dichloro-5-nitropyrimidine. All these compounds are pharmacologically significant scaffolds of the great importance of medicinal chemists. The fast and efficient synthetic methodology is highly desirable for defining their structure-activity relationship (SAR) and optimizing pharmacokinetic properties. Our research efforts utilize simple synthetic methods to generate a library of analogues for future SAR studies. The efficiency of our approach was exemplified in various pteridinones as well as pyrimidodiazepinones.
- MeSH
- léčivé přípravky chemie MeSH
- polymery chemie MeSH
- pteridiny chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
- MeSH
- aplikace orální MeSH
- gastrointestinální trakt metabolismus MeSH
- interakce mezi potravou a léky MeSH
- intestinální absorpce * MeSH
- léčivé přípravky chemie metabolismus MeSH
- lidé MeSH
- počítačová simulace MeSH
- příprava léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
1. elektronické vydání 1 online zdroj (136 stran)
Praktická cvičení jsou důležitou součástí výuky oboru farmaceutické technologie, v nichž posluchači farmaceutické fakulty získávají základní znalosti a dovednosti v přípravě lékových forem.Učebnice je rozdělena podle technologických specifik léčivých přípravků a je uspořádána od jednodušších forem představovaných homogenními soustavami (roztoky a speciální druhy roztoků), přes koloidní disperze (slizy a gely), k hrubým disperzím (suspenze, emulze). Základní poznatky jsou uplatňovány a rozvíjeny u polotuhých (masti, krémy, pasty) a pevných přípravků (čípky, vaginální kuličky, perorální prášky, zásypy).Součástí textu je kapitola o inkompatibilitách, tabulky emulgátorů a tabulka rozpustnosti vybraných léčivých a pomocných látek. Pozornost je zaměřena na tři hlavní aspekty přípravy: znalost požadavků kladených na danou lékovou formu; osvojení si správných technik a základních principů práce ve farmaceutické laboratoři; pochopení základních technologických principů a přístupů uplatňovaných při přípravě léčivých přípravků pro různé aplikační cesty.Nedílnou součástí je posouzení kritických faktorů, ovlivňujících jakost léčivého přípravku s ohledem na jeho stabilitu, mikrobiologickou jakost a účinnost léčiva, výběr vhodného obalu a určení doby použitelnosti přípravku.
- Klíčová slova
- Farmacie, farmakologie,
- MeSH
- chemie farmaceutická MeSH
- farmaceutická technologie metody MeSH
- léčivé přípravky chemie MeSH
- studium farmacie vysokoškolské MeSH
- NLK Obory
- farmacie a farmakologie
The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. p-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and difficult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was difficult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities.
