With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (Tgs) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-Tg glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R2 = 0.96). In contrast, the high-Tg glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (cmax) during in vitro dissolution (onset temperature R2 = 0.98; peak temperature R2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high Tg. The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.
Spray drying and hot-melt extrusion are among the most prevalent preparation techniques used in the pharmaceutical industry to produce amorphous solid dispersions (ASDs). This study advances previous research by integrating sample production, comprehensive analytical characterization, intrinsic dissolution rate measurements, and assessments of the behavior of ASDs under elevated temperature and humidity conditions. The study focuses on indomethacin, a widely used model for poorly soluble drugs, processed with PVP K30 or HPMC E5, both commonly used polymers. The findings demonstrate that hot-melt extruded samples exhibit superior stability against recrystallization, whereas spray dried samples achieve higher intrinsic dissolution rates. Furthermore, PVP K30 significantly outperforms HPMC E5 in the co-processing of indomethacin, enhancing both the intrinsic dissolution rate and the stability.
- MeSH
- deriváty hypromelózy chemie MeSH
- farmaceutická chemie metody MeSH
- indomethacin * chemie MeSH
- krystalizace * MeSH
- povidon chemie MeSH
- příprava léků metody MeSH
- rozpustnost * MeSH
- sprejové sušení * MeSH
- stabilita léku * MeSH
- technologie extruze tavenin * metody MeSH
- uvolňování léčiv MeSH
- vlhkost MeSH
- vysoká teplota MeSH
- vysoušení metody MeSH
- Publikační typ
- časopisecké články MeSH
In recent years, CM has become increasingly popular in the pharmaceutical industry for the production of OSD forms. Most of the newly developed APIs nowadays are extremely cohesive and sticky with a mean particle size particle of <100 μm, a wide PSD and a high tendency to agglomerate, making them difficult to accurately dose using loss-in-weight equipment during CM. In this research paper, the effect of various glidants on the volumetric and gravimetric feeding of several APIs was assessed. Three challenging API (APAPμ, MPT and SD) and four different glidants (Aerosil® 200, Aerosil® R972, Syloid® 244FP and TRI-CAFOS® 200-7) were selected. For all feeding trials, a GEA CF equipped with 20 mm concave screws was used, in combination with an external catch scale. The volumetric feeding trials showed the ability of each glidant to increase the FFmax and reduce the FFmovRSD40 and the FFdecay for the cohesive APIs (APAPμ and MPT). Although the fumed silica grades showed the highest impact on the previously mentioned feeding parameters, low AE10 values were obtained, negatively affecting the feeding performance at higher glidant concentration. Both Syloid 244FP and TCP were good alternatives. However, to obtain a similar feeding performance a higher concentration of these glidants is required. The volumetric trials showed that glidant addition has no additional benefits for APIs with good flow properties such as SD. The second part of this paper discussed the impact of glidant addition on the gravimetric feeding behavior of the cohesive powders. Both the fumed silica grades (Aerosil® 200 and Aerosil® R972) and Syloid 244FP lowered the deviation on all LC% profiles of the cohesive APIs. In contrast to the volumetric trails, blends with excess fumed silica resulted in low AE10 values which are efficiently dosed by the CF during the gravimetric feeding.
In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4 M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0 ± 125.4 mg/g in IBU:OctA THEDES, 1151.7 ± 22.2 mg/g in IBU:NonA, 1160.4 ± 33.5 mg/g in IBU:DeA, and 231.3 ± 10.7 mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8 ± 9.0 % to 64.2 ± 1.0 % for IBU and 5.0 ± 3.3 % to 19.4 ± 0.1 % for AbAc. This increased to between 60.4 ± 2.8 % and 79.4 ± 5.0 % of released IBU, and 23.6 ± 1.0 % to 57.3 ± 5.8 % of released AbAc, with 20 % (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.
- MeSH
- abirateron * chemie aplikace a dávkování MeSH
- farmaceutická chemie metody MeSH
- fixní kombinace léků MeSH
- ibuprofen * chemie aplikace a dávkování MeSH
- mastné kyseliny chemie MeSH
- příprava léků metody MeSH
- protinádorové látky chemie aplikace a dávkování MeSH
- rozpouštědla * chemie MeSH
- rozpustnost * MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
Nowadays, most of the newly developed active pharmaceutical ingredients (APIs) consist of cohesive particles with a mean particle size of <100μm, a wide particle size distribution (PSD) and a tendency to agglomerate, therefore they are difficult to handle in continuous manufacturing (CM) lines. The current paper focuses on the impact of various glidants on the bulk properties of difficult-to-handle APIs. Three challenging powders were included: two extremely cohesive APIs (acetaminophen micronized (APAPμ) and metoprolol tartrate (MPT)) which previously have shown processing issues during different stages of the continuous direct compression (CDC)-line and a spray dried placebo (SD) powder containing hydroxypropylmethyl cellulose (HPMC), known for its sub-optimal flow with a high specific surface area (SSA) and low density. Four flow-enhancing excipients were used: a hydrophilic (Aerosil® 200) and hydrophobic (Aerosil® R972) fumed silica grade, a mesoporous silica grade (Syloid® 244FP), and a calcium phosphate excipient (TRI-CAFOS® 200-7). The APIs and binary API/glidant blends (varied between 0.5-2.75 w/w%) were characterized for their bulk properties relevant for CDC. The results indicated that optimizing different bulk parameters (e.g., density, flow, compressibility..) of an API required varying weight percentages of the glidant (e.g., different surface area coverage (SAC)) depending on the APIs. Moreover, even at similar SAC, the impact of the glidant on the bulk characteristic of the APIs depended on the glidant type properties. While nano-sized silicon dioxide were effective for improving the flowability of a powder, other glidants (mesoporous silica and tricalcium phosphate (TCP)) showed also promise as alternatives. Additionally, an excess of glidant, referred to as oversilication, negatively impacted some bulk parameters, but other characteristics were unaffected. Finally, to determine the appropriate concentration of the different classes of glidants, SAC calculations, an understanding of the glidant's working mechanism, and knowledge about the API's characteristics (i.e., morphology, compressibility, flowability, aeration, density, and wall friction) are required. This study confirmed the necessity of including various material characterization techniques to assess the impact of glidants on the bulk characteristics of APIs.
- MeSH
- deriváty hypromelózy * chemie MeSH
- farmaceutická chemie metody MeSH
- fosforečnany vápenaté * chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- metoprolol * chemie MeSH
- nerozplněné léky MeSH
- oxid křemičitý chemie MeSH
- paracetamol * chemie MeSH
- pomocné látky * chemie MeSH
- prášky, zásypy, pudry * MeSH
- příprava léků metody MeSH
- reologie * MeSH
- velikost částic * MeSH
- Publikační typ
- časopisecké články MeSH
V článku je zpracována problematika empirické perorální antibiotické terapie nejčastějších akutních komunitních bakteriální infekcí u dětí, a sice tonzilitidy, otitis media, sinusitidy, pneumonie, cystitidy, pyelonefritidy, erysipelu, flegmóny, impetiga a erythema migrans. Kromě antibiotik první volby jsou uvedeny i alternativy při výpadku antibiotik nebo při alergii. Součástí doporučení jsou také magistraliter receptury vybraných antibiotik. V článku je dále věnována pozornost klasifikaci antibiotik AWaRe, která rozděluje dostupná antibiotika do tří skupin podle rizika indukce rezistence bakterií.
This article addresses the issue of empirical oral antibiotic therapy for the most common acute community-acquired bacterial infections in children, specifically tonsillitis, otitis media, sinusitis, pneumonia, cystitis, pyelonephritis, erysipelas, cellulitis, impetigo, and erythema migrans. In addition to first-choice antibiotics, alternatives are provided in cases of antibiotic shortages or allergies. The recommendations also include magistral (compounded, pharmacist-prepared) formulas for selected antibiotics. The article further focuses on the AWaRe classification of antibiotics, which divides available antibiotics into three groups according to the risk of inducing bacterial resistance.
- MeSH
- antibakteriální látky * farmakologie klasifikace terapeutické užití MeSH
- antibiotická rezistence MeSH
- bakteriální infekce * epidemiologie farmakoterapie klasifikace MeSH
- bakteriální pneumonie farmakoterapie MeSH
- dítě MeSH
- impetigo etiologie farmakoterapie klasifikace MeSH
- lidé MeSH
- otitis media farmakoterapie klasifikace MeSH
- příprava léků klasifikace metody MeSH
- sinusitida farmakoterapie MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- tonzilitida farmakoterapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
Sildenafil citrate has low oral bioavailability, systemic adverse effects, and a relatively delayed action. These issues may be addressed through direct transdermal delivery to the penis. This study aims to investigate the microemulsion formulation of the drug for effective transdermal delivery. Sildenafil citrate was formulated as a microemulsion using clove oil, dimethyl sulphoxide, phosphate buffer (pH 7), propylene glycol, Tween®80, and distilled water. Different proportions of these components were used to create six formulations of the microemulsion (F1-F6), which were then characterised by their physical appearance and clarity, pH, viscosity, conductivity, percent transmission, and droplet size. Furthermore, the stability, content analysis, in-vitro drug release, and transdermal permeation of sildenafil citrate from the generated drug-loaded microemulsions were studied. All prepared formulas contained nano-sized oil droplets (less than 20 nm), and the pH values were within the range of skin pH; however, two formulas were not transparent. Additionally, all formulations were thermodynamically stable, passing freeze-thaw, heating-cooling, and centrifugation tests. Next, the formulas demonstrated zero-order release kinetics, indicating that they can provide a sustained release profile for sildenafil citrate. Finally, the microemulsion formulation exhibited a 2.8-fold enhancement in skin permeation compared with that of the sildenafil citrate suspension. The prepared microemulsions demonstrated beneficial physical properties and skin permeation profiles that are promising for the local administration of sildenafil citrate.
- Klíčová slova
- mikroemulze,
- MeSH
- aplikace kožní * MeSH
- emulze MeSH
- hřebíčkový olej MeSH
- krysa rodu rattus MeSH
- lékové formy MeSH
- modely u zvířat MeSH
- permeabilita MeSH
- příprava léků metody MeSH
- sildenafil citrát * aplikace a dávkování farmakokinetika farmakologie MeSH
- stabilita léku MeSH
- suspenze MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- klinická studie MeSH
The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.
- MeSH
- aplikace orální MeSH
- biologická dostupnost * MeSH
- dospělí MeSH
- inhibitory faktoru Xa farmakokinetika aplikace a dávkování MeSH
- interakce mezi potravou a léky * MeSH
- jídla MeSH
- klinické křížové studie * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- omezení příjmu potravy * MeSH
- příprava léků metody MeSH
- rivaroxaban * farmakokinetika aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release.
- MeSH
- farmaceutická chemie metody MeSH
- hydrofobní a hydrofilní interakce * MeSH
- kyseliny laurové chemie MeSH
- lipidy * chemie MeSH
- oleje chemie MeSH
- polysorbáty chemie MeSH
- povrchově aktivní látky * chemie MeSH
- příprava léků * metody MeSH
- rozpouštědla * chemie MeSH
- rozpustnost * MeSH
- simulace molekulární dynamiky * MeSH
- sulfonamidy chemie aplikace a dávkování MeSH
- uvolňování léčiv * MeSH
- Publikační typ
- časopisecké články MeSH
Inhalation drug administration is increasingly used for local pharmacotherapy of lung disorders and as an alternative route for systemic drug delivery. Modern inhalation powder systems aim to target drug deposition in the required site of action. Large porous particles (LPP), characterized by an aerodynamic diameter over 5 μm, density below 0.4 g/cm3, and the ability to avoid protective lung mechanisms, come to the forefront of the research. They are mostly prepared by spray techniques such as spray drying or lyophilization using pore-forming substances (porogens). These substances could be gaseous, solid, or liquid, and their selection depends on their polarity, solubility, and mutual compatibility with the carrier material and the drug. According to the pores-forming mechanism, porogens can be divided into groups, such as osmogens, extractable porogens, and porogens developing gases during decomposition. This review characterizes modern trends in the formulation of solid microparticles for lung delivery; describes the mechanisms of action of the most often used porogens, discusses their applicability in various formulation methods, emphasizes spray techniques; and documents discussed topics by examples from experimental studies.
- MeSH
- aplikace inhalační MeSH
- farmaceutická chemie metody MeSH
- lékové transportní systémy * metody MeSH
- lidé MeSH
- plíce * metabolismus účinky léků MeSH
- poréznost MeSH
- prášky, zásypy, pudry MeSH
- příprava léků metody MeSH
- velikost částic * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
