Treating oral diseases remains challenging as API is quickly washed out of the application site by saliva turnover and mouth movements. In situ gels are a class of application forms that present sol-gel transition's ability as a response to stimuli. Their tunable properties are provided using smart polymers responsible for stimuli sensitivity, often providing mucoadhesivity. In this study, antimicrobial in situ gels of thermosensitive and pH-sensitive polymers loaded with silver nanoparticles were prepared and evaluated. The nanoparticles were prepared by green synthesis using Agrimonia eupatoria L. extract. According to the data analysis, the in situ gel with the most promising profile contained 15 % of Pluronic® F-127, 0.25 % of methylcellulose, and 0.1 % of Noveon® AA-1. Pluronic® F-127 and methylcellulose significantly increased the viscosity of in situ gels at 37 °C and shear rates similar to speaking and swallowing. At 20 °C, a behavior close to a Newtonian fluid was observed while being easily injectable (injection force 13.455 ± 1.973 N). The viscosity of the formulation increased with temperature and reached 2962.77 ± 63.37 mPa·s (37 °C). A temperature increase led to increased adhesiveness and rigidity of the formulation. The critical sol-gel transition temperature at physiological pH was 32.65 ± 0.35 °C. 96.77 ± 3.26 % of Ag NPs were released by erosion and dissolution of the gel after 40 min. The determination of MIC showed effect against E. coli and S. aureus (0.0625 mM and 0.5000 mM, respectively). The relative inhibition zone diameter of the in situ gel was 73.32 ± 11.06 % compared to gentamicin sulfate. This work discusses the optimization of the formulation of novel antibacterial in situ gel for oromucosal delivery, analyses the impact of the concentration of excipients on the dependent variables, and suggests appropriate evaluation of the formulation in terms of its indication. This study offers a promising dosage form for local treatment of oral diseases.
Inhalační podání suchých práškových částic je využívanou aplikační cestou pro dosažení lokálního i systémového působení léčiv. U plicních onemocnění je žádoucí depozice léčiv v místě účinku. Pro efektivní léčbu jsou tak zásadní parametry inhalovaných částic, a to především jejich velikost, tvar nebo aerosolizační parametry. Vhodných parametrů je možné dosáhnout volbou metody přípravy nebo pomocných látek (nosičů, porogenů nebo aerosolizačních činidel). Cílem experimentu byla příprava jedenácti šarží práškových směsí sprejovým sušením, které se lišily použitým nosičem, množstvím leucinu či porogenu. Cílem bylo optimalizovat složení pro navázání léčiva s ohledem na požadavky pro plicní podání. Připravené částice byly zhodnoceny z hlediska morfologie, tokových vlastností, pórovitosti, geometrického i aerodynamického průměru. Bylo zjištěno, že se zvyšující se koncentrací leucinu se sypná hustota částic snižovala a zároveň rostla hodnota FPF. Stejně tak docházelo i ke snižování MMAD. Jako vhodná se jevila šarže obsahující 15 % leucinu. Při stanovení optimální koncentrace porogenu (hydrogenuhličitan amonný) u manitolových částic dosahovala nejlepších výsledků šarže s jeho 1% zastoupením, vzhledem k vyhovující velikosti částic oproti ostatním šaržím (MMAD 5,92 ± 1,32 μm), vhodné pórovitosti a obecně přijatelné morfologii částic. Za účelem formulace částic s navázaným léčivem by tedy bylo vhodné snížit aerodynamický průměr částic např. úpravou procesních parametrů sprejového sušení.
Inhalation administration of dry powder particles is a common application route to achieve local and systemic drug effects. For pulmonary diseases, the deposition of drugs at the site of action is desirable. Thus, the parameters of the inhaled particles, especially their size, shape, or aerosolization, are essential for effective treatment. Suitable parameters can be achieved by choice of preparation method or excipients (carriers, porogens, or aerosolizing agents). This experiment aimed to prepare 11 batches of powder mixtures by spray drying, which differed in the carrier used and the amount of leucine or porogen. The aim was to optimize the formulation for drug binding concerning the requirements for pulmonary administration. The prepared particles were evaluated in terms of morphology, flow properties, porosity, and geometric and aerodynamic diameter. It was found that with increasing concentration of leucine, the bulk density of the particles decreased while the FPF value increased. Similarly, there was a decrease in MMAD. The batch containing 15% leucine was the most suitable. In determining the optimum porogen concentration for mannitol particles, the batch with its 1% gave the best results due to its adequate particle size compared to the other batches (MMAD 5.92 ± 1.32 μm), suitable porosity, and particle morphology. Thus, to formulate drug-loaded particles, it would be advisable to reduce the aerodynamic diameter of the particles, e.g., by spray drying process parameters.
Neterapeutické užívání léčiv a jeho nárůst představují celosvětový a celospolečenský problém. Tento zasahuje nejen do oblasti zdravotnictví, ale má i značný lidský, sociální a ekonomický dopad. Vývoj lékových forem (LF) omezujících nebo zabraňujících zneužití léčiv je jedním z kroků komplexního řešení tohoto problému. Za poslední desetiletí došlo k vývoji odolnějších LF, které jsou schopné zneužívání léčivých přípravků (LP) omezit. Technologie a strategie zabraňující zneužívání LP se zaměřují většinou na obvyklé nebo očekávané aplikační cesty využívané při zneužití. Technologicky je možné omezit extrahovatelnost účinné látky, biologickou dostupnost po manipulaci s LF, zabránit distribuci léčiva v organismu po užití alternativní aplikační cesty, snížit účinek látky po manipulaci, případně účinek znepříjemnit. Nejčastěji se technologický přístup zaměřuje na formulace fyzikálně a chemicky odolných přípravků, které jsou často také schopny modifikovat farmakokinetiku léčiva po nežádoucí manipulaci. Postupně se do praxe prosazují i další možnosti, jako je použití antagonistů léčiv, proléčiv, averzivních látek a využití inovativních excipientů.
The non-therapeutic use of medicines and its increase is a global and societal problem. It affects not only the health sector, but it also has significant human, social and economic consequences. The development of dosage forms (DFs) to reduce or prevent the abuse of medicines is one step in a comprehensive solution to this problem. The last decade has brought the development of more robust DFs capable of reducing drug abuse. Technologies and strategies to prevent drug abuse typically target common or expected application routes. Technology can limit the extractability of the active ingredient and the bioavailability after DF manipulation, prevent drug distribution in the body after using an alternative administration route, reduce the effect of the substance after manipulation, or make the effect less pleasant. The technological approach often focuses on formulations that are physically and chemically resistant, often also capable of modifying the drug's pharmacokinetics after adverse manipulation. Other options, such as drug antagonists, prodrugs, aversive agents, and innovative excipients, are also gaining attention.
The direct tailoring of the size, composition, or number of layers belongs to the advantages of 3D printing employment in producing orodispersible films (ODFs) compared to the frequently utilized solvent casting method. This study aimed to produce porous ODFs as a substrate for medicated ink deposited by a 2D printer. The innovative semi-solid extrusion 3D printing method was employed to produce multilayered ODFs, where the bottom layer assures the mechanical properties. In contrast, the top layer provides a porous structure for ink entrapment. Hydroxypropyl methylcellulose and polyvinyl alcohol were utilized as film-forming polymers, glycerol as a plasticizer, and sodium starch glycolate as a disintegrant in the bottom matrix. Several porogen agents (Aeroperl® 300, Fujisil®, Syloid® 244 FP, Syloid® XDP 3050, Neusilin® S2, Neusilin® US2, and Neusilin® UFL2) acted as porosity enhancers in the two types of top layer. ODFs with satisfactory disintegration time were prepared. The correlation between the porogen content and the mechanical properties was proved. A porous ODF structure was detected in most samples and linked to the porogen content. SSE 3D printing represents a promising preparation method for the production of porous ODFs as substrates for subsequent drug deposition by 2D printing, avoiding the difficulties arising in casting or printing medicated ODFs directly.
- Publikační typ
- časopisecké články MeSH
Inhalation is used for local therapy of the lungs and as an alternative route for systemic drug delivery. Modern powder inhalation systems try to target the required site of action/absorption in the respiratory tract. Large porous particles (LPPs) with a size >5 μm and a low mass density (usually measured as bulk or tapped) of <0.4 g/cm3 can avoid protective lung mechanisms. Their suitable aerodynamic properties make them perspective formulations for deep lung deposition. This experiment studied the effect of spray-drying process parameters on LPP properties. An experimental design of twelve experiments with a central point was realized using the Box-Behnken method. Three process parameters (drying temperature, pump speed, and air speed) were combined on three levels. Particles were formed from a D-mannitol solution, representing a perspective material for lung microparticles. The microparticles were characterized in terms of physical size (laser diffraction), aerodynamic diameter (aerodynamic particle sizer), morphology (SEM), and densities. The novelty and main goal of this research were to describe how the complex parameters of the spray-drying process affect the properties of mannitol LPPs. New findings can provide valuable data to other researchers, leading to the easy tuning of the properties of spray-dried particles by changing the process setup.
- Publikační typ
- časopisecké články MeSH
Formulace mikročástic složených ze směsi nosičů představuje inovativní přístup pro podání léčiv do plic ve formě suchého prášku. Použité nosiče mohou významně ovlivnit výsledné vlastnosti mikročástic, jako je velikost, tvar, povrch, hygroskopicita či agregace, a tím zlepšit aerosolizaci léčiv po jejich inhalaci. Zmíněné vlastnosti jsou klíčové pro efektivní pulmonální terapii. Kombinací nosičů povahy sacharidů a gelujících látek je výhodné pro řízené uvolňování léčiva. Cílem experimentální práce bylo sprejovým sušením připravit a následně zhodnotit několik šarží mikročástic složených z nosičů na bázi cukrů (manitol, maltodextrin, dextran) a gelujících sacharidů (chitosan, chondroitin-sulfát) a vybrat vhodnou kombinaci pro navazující experimentální práce zaměřené na inkorporaci léčiva do mikročásticové matrice. Nejvhodnější parametry vykazovaly šarže, jejichž aerodynamický průměr se blížil 5 μm, a to částice připravené z kombinace manitolu a dextranu, chitosanu a chondroitinu nebo maltodextrinu a chondoitinu. U těchto šarží byla také naměřena nejvyšší hodnota frakce jemných částic (> 43 %). Z pohledu zpracovatelnosti je vhodná šarže se zastoupením maltodextrinu a chondroitinu vzhledem k nižší viskozitě vstupní disperze a pravidelnějšímu tvaru finálních mikročástic.
The formulation of microparticles composed of a mixture of carriers represents an innovative approach for lung drug delivery of dry powder. The carriers used can significantly influence the properties of the microparticles, such as size, shape, surface area, hygroscopicity, or aggregation, thus improving the aerosolization of the drugs after inhalation. The properties mentioned above are crucial for effective pulmonary therapy. The combination of carriers of a carbohydrate nature and gelling agents is advantageous for controlled drug release. The experimental work aimed to prepare by spray drying and subsequently evaluate ten batches of microparticles composed of sugar-based carriers (mannitol, maltodextrin, dextran) and gelling polymers (chitosan, chondroitin sulfate) and to select a suitable combination for follow-up experimental work aimed at drug incorporation into the microparticle matrix. The most suitable parameters were exhibited by batches whose aerodynamic diameter was close to 5 μm, particles prepared from a combination of mannitol and dextran, chitosan and chondroitin, or maltodextrin and chondroitin. These batches also showed the highest fine particle fraction value (> 43%). From a processability point of view, the batch with maltodextrin and chondroitin is preferable due to the lower viscosity of the dispersion and the more regular shape of the final microparticles.
- MeSH
- aplikace inhalační MeSH
- farmaceutický výzkum MeSH
- lidé MeSH
- mikroplasty MeSH
- nosiče léků * MeSH
- sprejové sušení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
High specific surface area (SSA), porous structure, and suitable technological characteristics (flow, compressibility) predetermine powder carriers to be used in pharmaceutical technology, especially in the formulation of liquisolid systems (LSS) and solid self-emulsifying delivery systems (s-SEDDS). Besides widely used microcrystalline cellulose, other promising materials include magnesium aluminometasilicates, mesoporous silicates, and silica aerogels. Clay minerals with laminar or fibrous internal structures also provide suitable properties for liquid drug incorporation. This work aimed at a comparison of 14 carriers' main properties. Cellulose derivatives, silica, silicates, and clay minerals were evaluated for flow properties, shear cell experiments, SSA, hygroscopicity, pH, particle size, and SEM. The most promising materials were magnesium aluminometasilicates, specifically Neusilin® US2, due to its proper flow, large SSA, etc. Innovative materials such as FujiSil® or Syloid® XDP 3050 were for their properties evaluated as suitable. The obtained data can help choose a suitable carrier for formulations where the liquid phase is incorporated into the solid dosage form. All measurements were conducted by the same methodology and under the same conditions, allowing a seamless comparison of property evaluation between carriers, for which available company or scientific sources do not qualify due to different measurements, conditions, instrumentation, etc.
- Publikační typ
- časopisecké články MeSH
The deposition of a drug to its required destination is crucial for effective lung treatment. It is important to design a suitable formulation that delivers the active ingredient to the desired site and resists the natural cleansing mechanisms of the airways. Large porous particles used as active substance carriers appear to be the most effective option for lung drug delivery. The present article provides a basic overview of the mechanisms of deposition of dry inhalable powders and methods of their preparation and evaluation. Spray drying together with micronization and crystallization techniques are among the most used methods of preparation of the discussed particles. Besides, these techniques can be combined with other production processes (encapsulation, emulsification, etc.). The evaluation of the properties of particles suitable for pulmonary application is based on specific requirements for their density, porosity, shape, aerodynamic parameters, and deposition in the lungs, which can now be simulated on an accurate model of artificial lungs.
- MeSH
- aplikace inhalační MeSH
- lékové formy * MeSH
- lidé MeSH
- prášky, zásypy, pudry MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Orodispersible films are an innovative dosage form. Their main advantages are the application comfort and the possibility of personalization. This work aimed to evaluate the influence of different drying times on the properties of orodispersible films of various thicknesses, prepared in two different semisolid extrusion 3D printing setups. In the first experiment, drying times were dependent on the overall print time of each batch. In the second setup, the drying time was set equal according to the longest one. The evaluated parameters were films' weight uniformity, thickness, moisture content, surface pH, disintegration time, hardness, and tensile strength. Upon statistical comparison, significant differences in the moisture content were found, subsequently affecting the disintegration time. Moreover, statistically significant differences in films' mechanical properties (hardness, tensile strength) were also described, proving that moisture content simultaneously affects film plasticity and related properties. In conclusion, a mutual comparison of the manufactured orodispersible films showed that the drying time affects their physical and mechanical properties. The in-process drying setup was proved to be sufficient while allowing quicker manufacturing.
- Publikační typ
- časopisecké články MeSH
A method of preparing tablets called liquisolid technique is currently emerging. In these formulations, an important role is played by porous carriers, which are the basic building blocks of liquisolid systems (LSSs). The most common are microcrystalline cellulose (MCC), magnesium aluminometasilicates, silica aerogels, mesoporous silicates, clays, etc. In this study, magnesium aluminometasilicate is used to prepare modified LSS formulations with plant extracts as model drugs dissolved in water (W) or ethanol (E). The modification involves drying tablets in a microwave (MW) and hot air dryer (HA) for a specified period. Powder blends and tablets were evaluated for physical properties, and their antioxidant activity (AA) was measured in a modified dissolution by ferric reducing antioxidant power assay (FRAP). PLS and ANOVA were used to compare tablets properties depending on the composition and technology. The experiment is based on a previous one, in which the plant extracts were processed into tablets using a similar method. Therefore, extending the study to include more plants and the robust statistical evaluation and comparison of the products was a procedure to justify the suitability of the presented method for a wide range of liquid plant extracts. As a result, we obtained tablets with excellent physical properties, including a short disintegration and dissolution, which is problematic in tableted extracts.
- Publikační typ
- časopisecké články MeSH
